Hubbry Logo
PARP1PARP1Main
Open search
PARP1
Community hub
PARP1
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
PARP1
PARP1
PARP1
View on Wikipedia
from Wikipedia
PARP1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPARP1, ADPRT, ADPRT 1, ADPRT1, ARTD1, PARP, PARP-1, PPOL, pADPRT-1, poly(ADP-ribose) polymerase 1, Poly-PARP, PARS
External IDsOMIM: 173870; MGI: 1340806; HomoloGene: 1222; GeneCards: PARP1; OMA:PARP1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

142

11545

Ensembl

ENSG00000143799

ENSMUSG00000026496

UniProt

P09874

P11103

RefSeq (mRNA)

NM_001618

NM_007415

RefSeq (protein)

NP_001609
NP_001609.2

n/a

Location (UCSC)Chr 1: 226.36 – 226.41 MbChr 1: 180.4 – 180.43 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene.[5] It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family.[6] PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.[7]

Function

[edit]

PARP1 works:

  • By using NAD+ to synthesize poly ADP ribose (PAR) and transferring PAR moieties to proteins (ADP-ribosylation).[8]
  • In conjunction with BRCA, which acts on double strands; members of the PARP family act on single strands; or, when BRCA fails, PARP takes over those jobs as well (in a DNA repair context).

PARP1 is involved in:

PARP1 is activated by:

Role in DNA damage repair

[edit]

PARP1 acts as a first responder that detects DNA damage and then facilitates choice of repair pathway.[12] PARP1 contributes to repair efficiency by ADP-ribosylation of histones leading to decompaction of chromatin structure, and by interacting with and modifying multiple DNA repair factors.[6] PARP1 is implicated in the regulation of several DNA repair processes including the pathways of nucleotide excision repair, non-homologous end joining, microhomology-mediated end joining, homologous recombinational repair, and DNA mismatch repair.[12]

PARP1 has a role in repair of single-stranded DNA (ssDNA) breaks. Knocking down intracellular PARP1 levels with siRNA or inhibiting PARP1 activity with small molecules reduces repair of ssDNA breaks. In the absence of PARP1, when these breaks are encountered during DNA replication, the replication fork stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via homologous recombination (HR) repair, a potentially error-free repair mechanism. For this reason, cells lacking PARP1 show a hyper-recombinagenic phenotype (e.g., an increased frequency of HR),[13][14][15] which has also been observed in vivo in mice using the pun assay.[16] Thus, if the HR pathway is functioning, PARP1 null mutants (cells without functioning PARP1) do not show an unhealthy phenotype, and in fact, PARP1 knockout mice show no negative phenotype and no increased incidence of tumor formation.[17]

Role in inflammation

[edit]

PARP1 is required for NF-κB transcription of proinflammatory mediators such as tumor necrosis factor, interleukin 6, and inducible nitric oxide synthase.[9][18] PARP1 activity contributes to the proinflammatory macrophages that increase with age in many tissues.[19] ADP-riboyslation of the HMGB1 high-mobility group protein by PARP1 inhibits removal of apoptotic cells, thereby sustaining inflammation.[20]

In asthma PARP1 facilitates recruitment and function of immune cells, including CD4+ T-cells, eosinophils, and dendritic cells.[18]

Over-expression in cancer

[edit]

PARP1 is one of six enzymes required for the highly error-prone DNA repair pathway microhomology-mediated end joining (MMEJ).[21] MMEJ is associated with frequent chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements. When PARP1 is up-regulated, MMEJ is increased, causing genome instability.[22] PARP1 is up-regulated and MMEJ is increased in tyrosine kinase-activated leukemias.[22]

PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer,[23] BRCA-mutated ovarian cancer,[24] and BRCA-mutated serous ovarian cancer.[25]

PARP1 is also over-expressed in a number of other cancers, including neuroblastoma,[26] HPV infected oropharyngeal carcinoma,[27] testicular and other germ cell tumors,[28] Ewing's sarcoma,[29] malignant lymphoma,[30] breast cancer,[31] and colon cancer.[32]

Cancers are very often deficient in expression of one or more DNA repair genes, but over-expression of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary cancer syndromes).[citation needed] (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.[citation needed] (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damage which, through replication errors (translesion synthesis), lead to mutations and cancer. However, PARP1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

Interaction with BRCA1 and BRCA2

[edit]

Both BRCA1 and BRCA2 are at least partially necessary for the HR pathway to function. Cells that are deficient in BRCA1 or BRCA2 have been shown to be highly sensitive to PARP1 inhibition or knock-down, resulting in cell death by apoptosis, in stark contrast to cells with at least one good copy of both BRCA1 and BRCA2. Many breast cancers have defects in the BRCA1/BRCA2 HR repair pathway due to mutations in either BRCA1 or BRCA2, or other essential genes in the pathway (the latter termed cancers with "BRCAness"). Tumors with BRCAness are hypothesized to be highly sensitive to PARP1 inhibitors, and it has been demonstrated in mice that these inhibitors can both prevent BRCA1/2-deficient xenografts from becoming tumors and eradicate tumors having previously formed from BRCA1/2-deficient xenografts.

Application to cancer therapy

[edit]

PARP1 inhibitors are being tested for effectiveness in cancer therapy.[33] It is hypothesized that PARP1 inhibitors may prove highly effective therapies for cancers with BRCAness, due to the high sensitivity of the tumors to the inhibitor and the lack of deleterious effects on the remaining healthy cells with functioning BRCA HR pathway. This is in contrast to conventional chemotherapies, which are highly toxic to all cells and can induce DNA damage in healthy cells, leading to secondary cancer generation.[34][35]

Aging

[edit]

PARP activity (which is mainly due to PARP1) measured in the permeabilized mononuclear leukocyte blood cells of thirteen mammalian species (rat, guinea pig, rabbit, marmoset, sheep, pig, cattle, pigmy chimpanzee, horse, donkey, gorilla elephant and man) correlates with maximum lifespan of the species.[36] Lymphoblastoid cell lines established from blood samples of humans who were centenarians (100 years old or older) have significantly higher PARP activity than cell lines from younger (20 to 70 years old) individuals.[37] The Wrn protein is deficient in persons with Werner syndrome, a human premature aging disorder. PARP1 and Wrn proteins are part of a complex involved in the processing of DNA breaks.[38] These findings indicate a linkage between longevity and PARP-mediated DNA repair capability. Furthermore, PARP can also act against production of reactive oxygen species, which may contribute to longevity by inhibiting oxidative damage to DNA and proteins.[39] These observations suggest that PARP activity contributes to mammalian longevity, consistent with the DNA damage theory of aging.[citation needed]

PARP1 appears to be resveratrol's primary functional target through its interaction with the tyrosyl tRNA synthetase (TyrRS).[40] Tyrosyl tRNA synthetase translocates to the nucleus under stress conditions stimulating NAD+-dependent auto-poly-ADP-ribosylation of PARP1,[40] thereby altering the functions of PARP1 from a chromatin architectural protein to a DNA damage responder and transcription regulator.[41]

The messenger RNA level and protein level of PARP1 is controlled, in part, by the expression level of the ETS1 transcription factor which interacts with multiple ETS1 binding sites in the promoter region of PARP1.[42] The degree to which the ETS1 transcription factor can bind to its binding sites on the PARP1 promoter depends on the methylation status of the CpG islands in the ETS1 binding sites in the PARP1 promoter.[23] If these CpG islands in ETS1 binding sites of the PARP1 promoter are epigenetically hypomethylated, PARP1 is expressed at an elevated level.[23][24]

Cells from older humans (69 to 75 years of age) have a constitutive expression level of both PARP1 and PARP2 genes reduced by half, compared to their levels in young adult humans (19 to 26 years old). However, centenarians (humans aged 100 to 107 years of age) have constitutive expression of PARP1 at levels similar to those of young individuals.[43] This high level of PARP1 expression in centenarians was shown to allow more efficient repair of H2O2 sublethal oxidative DNA damage.[43] Higher DNA repair is thought to contribute to longevity (see DNA damage theory of aging). The high constitutive levels of PARP1 in centenarians were thought to be due to altered epigenetic control of PARP1 expression.[43]

Both sirtuin 1 and PARP1 have a roughly equal affinity for the NAD+ that both enzymes require for activity.[44] But DNA damage can increase levels of PARP1 more than 100-fold, leaving little NAD+ for SIRT1.[44]

Role in cell death

[edit]

Following severe DNA damage, excessive activation of PARP1 can lead to cell death.[45] Initially, overactivation of the enzyme was linked to apoptotic cell death[46][47] but later, PARP1-mediated cell death turned out to show characteristics of necrotic cell death (i.e. early plasma membrane disruption, structural and functional mitochondrial alterations).[48][49] These findings provided explanation for previous and subsequent reports demonstrating tissue protective effects of PARP inhibitors and the PARP1 knockout phenotypes in various models of ischemia-reperfusion injury (e.g. in stroke, in the heart and in the gut) where oxidative stress-induced cell death is a central cellular event.[50] Later, apoptosis inducing factor (AIF; a misnomer) was identified as a key mediator of the PARP1-mediated regulated necrotic cell death pathway termed parthanatos.[51]

Plant PARP1

[edit]

Plants have a PARP1 with substantial similarity to animal PARP1, and roles of poly(ADP-ribosyl)ation in plant responses to DNA damage, infection and other stresses have been studied.[52][53] Intriguingly, in Arabidopsis thaliana (and presumably other plants), PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis.[54] The plant PARP2 carries PARP regulatory and catalytic domains with only intermediate similarity to PARP1, and carries N-terminal SAP DNA binding motifs rather than the Zn-finger DNA binding motifs of plant and animal PARP1 proteins.[54]

Interactions

[edit]

PARP1 has been shown to interact with:

See also

[edit]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

PARP1

View on Grokipedia
from Grokipedia
Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional nuclear that serves as a primary sensor of DNA damage, catalyzing the transfer of ADP-ribose units from NAD⁺ to itself and other proteins in a process known as poly(ADP-ribosyl)ation (PARylation). This 113 kDa protein, encoded by the PARP1 gene on human , is essential for maintaining genomic integrity by facilitating various pathways, including (BER), (NER), single-strand break repair (SSBR), and aspects of double-strand break repair such as (NHEJ) and (HR). Upon detecting DNA breaks via its N-terminal containing fingers, PARP1 undergoes rapid activation, auto-PARylation, and recruitment of repair factors, thereby orchestrating the cellular response to genotoxic stress. Structurally, PARP1 consists of three main domains: an N-terminal DNA-binding domain (DBD) with three zinc fingers and a nuclear localization signal, a central automodification domain (AD) featuring a BRCT motif for protein interactions, and a C-terminal catalytic domain (CAT) responsible for ADP-ribosyl transferase activity. The DBD enables specific binding to DNA strand breaks, inducing a conformational change that stimulates catalytic hyperactivity, leading to the synthesis of branched poly(ADP-ribose) chains on target proteins like histones and repair enzymes such as XRCC1 and DNA ligase III. These PAR chains serve as scaffolds for recruiting additional repair machinery, modulating chromatin accessibility through relaxation and decondensation, which is critical for efficient damage resolution. Beyond repair, PARP1 influences transcription by acting as a co-activator or repressor at gene promoters, interacting with factors like NF-κB and TEF1, and contributing to euchromatin maintenance. PARP1's dysregulation is implicated in numerous pathologies, particularly cancer, where its upregulation in tumors with deficiencies (e.g., /2 mutations) makes it a prime therapeutic target. (PARPi), such as and niraparib, exploit by trapping PARP1 on DNA and preventing repair, leading to in deficient cells while sparing normal ones; these agents have received FDA approval for treating ovarian, , and cancers. Additionally, PARP1 participates in , pathways like parthanatos and via NAD⁺/ATP depletion, and processes such as epithelial-mesenchymal transition, underscoring its broad regulatory roles in cellular . As the founding member of a 17-protein PARP family, PARP1 accounts for over 90% of cellular PARylation activity, highlighting its central position in stress response signaling.

Molecular Structure and Biochemistry

Gene Organization and Expression

The PARP1 gene, encoding poly(ADP-ribose) polymerase 1, was first identified in 1963 as a nuclear capable of catalyzing the formation of poly(ADP-ribose) chains from NAD⁺ in response to DNA damage, with the polymer itself discovered shortly thereafter by independent groups. The gene was cloned in the late , with key publications in 1987 detailing the full-length cDNA sequence and confirming its role in poly(ADP-ribosyl)ation, marking a milestone in understanding its enzymatic function. In humans, the PARP1 gene is located on chromosome 1q42.12, spanning approximately 47.4 kb from position 226,360,691 to 226,408,093 (GRCh38 assembly). It consists of 23 exons, with the coding sequence distributed across most of these, reflecting a typical eukaryotic that includes untranslated regions at both ends. The promoter region is regulated primarily by transcription factors Sp1 and Sp3, which bind to GC-rich elements to drive basal transcription. PARP1 exhibits ubiquitous basal expression across tissues, with mRNA detectable in nearly all cell types due to its essential in DNA maintenance. Expression levels are elevated in specific tissues such as the testis, , and , where higher demands for and genomic stability are anticipated. The PARP1 is highly conserved evolutionarily, present across many eukaryotes including and metazoans, though absent in some lineages such as , underscoring its fundamental in DNA damage response. Within mammals, the protein sequence shows over 95% identity, indicating strong selective pressure to maintain function.

Protein Domains and Catalytic Activity

PARP1 is a modular protein consisting of three principal domains: the N-terminal (DBD), the central (AMD), and the C-terminal catalytic domain (CD). The DBD encompasses three motifs: Zn1 (residues 1–97), Zn2 (residues 124–200), and Zn3 (residues 215–242), which cooperatively recognize single-stranded breaks with high affinity, facilitating initial damage detection; Zn1 primarily contacts the DNA backbone, while Zn2 inserts into the break site. The AMD, spanning residues 373–525 and including a BRCT fold, serves as the primary site for auto-modification, with key acceptor residues such as Glu488 and Glu491 enabling attachment of ADP-ribose units. The CD (residues 526–1014) houses the , featuring the conserved (His862, Tyr896, Glu988) responsible for NAD⁺ binding and hydrolysis. The catalytic activity of PARP1 centers on poly(ADP-ribosyl)ation (PARylation), a where ADP-ribose units from NAD⁺ are sequentially transferred to acceptor proteins, including PARP1 itself, forming linear or branched poly(ADP-ribose) (PAR) chains. The reaction proceeds via nucleophilic attack by the acceptor residue (typically glutamate, aspartate, serine, or others) on the N-glycosidic bond of NAD⁺, releasing and yielding an initial mono(ADP-ribose) unit; subsequent elongations occur at the 2'-OH of the terminal , with branching possible at the 2″-OH. This can be represented as: NAD++(ADP-ribose)n−acceptor→(ADP-ribose)n+1−acceptor+nicotinamide\text{NAD}^+ + (\text{ADP-ribose})_n - \text{acceptor} \rightarrow (\text{ADP-ribose})_{n+1} - \text{acceptor} + \text{nicotinamide} DNA strand breaks allosterically activate PARP1 by inducing conformational changes that unfold an autoinhibitory helical subdomain in the CD, enhancing catalytic efficiency over 500-fold and enabling rapid PAR synthesis. Binding to damaged DNA occurs with a dissociation constant (K_d) of approximately 5.7 nM under physiological conditions, primarily mediated by the Zn1 and Zn2 fingers. Auto-PARylation on the AMD generates negatively charged PAR chains, typically 20–30 units long, which create electrostatic repulsion with DNA, leading to PARP1 dissociation from the repair site and preventing excessive NAD⁺ depletion. This self-regulatory mechanism ensures transient occupancy at damage sites, with chain lengths varying based on NAD⁺ availability and damage severity.

Core Biological Functions

DNA Damage Detection and Single-Strand Break Repair

PARP1 serves as a primary for single-strand DNA breaks (SSBs), which arise from endogenous oxidative damage, , or intermediates in (BER). The N-terminal zinc-finger domains (ZnF1 and ZnF2) of PARP1 bind directly to the free DNA ends at SSBs with high affinity, enabling rapid detection and recruitment to damage sites within seconds of lesion formation. This binding induces a conformational change in PARP1, allosterically activating its catalytic domain to synthesize poly(ADP-ribose) (PAR) chains from NAD⁺. Upon activation at SSBs, PARP1 catalyzes PARylation of itself (auto-PARylation) and nearby repair factors, creating a scaffold that coordinates BER. Specifically, PAR chains serve as docking sites for the scaffold protein XRCC1, which in turn recruits DNA polymerase β (pol β) for gap-filling synthesis and DNA ligase III for nick sealing, thereby assembling the core BER complex and significantly accelerating SSB repair rates compared to PARP1-deficient systems. This PAR-dependent recruitment ensures efficient processing of BER intermediates, such as 5'-deoxyribose phosphate residues, preventing persistent nicks that could escalate to more severe lesions. Deficiency in PARP1 leads to accumulation of unrepaired SSBs, which during S-phase replication encounter advancing forks, causing fork stalling and collapse into double-strand breaks. Experimental evidence from Parp1 mice demonstrates this vulnerability, as these animals exhibit profound to alkylating agents like N-methyl-N-nitrosourea, with embryonic fibroblasts showing profoundly reduced survival and elevated chromosomal aberrations due to unrepaired SSBs. Such findings underscore PARP1's indispensable role in maintaining genomic integrity through prompt SSB detection and BER facilitation.

Role in Double-Strand Break Repair and

PARP1 plays a supportive role in the repair of DNA double-strand breaks (DSBs) by facilitating alternative end-joining (alt-EJ) pathways, particularly (MMEJ), when canonical (NHEJ) or () is compromised. In scenarios where NHEJ factors like Ku are absent or HR is impaired, PARP1 binds to DSB ends and promotes error-prone joining through short microhomologies (typically 2-4 base pairs), leading to deletions at the repair junction. This backup mechanism ensures cellular survival but contributes to genomic instability due to its mutagenic nature. In HR, PARP1 aids initiation by synthesizing poly(ADP-ribose) (PAR) chains that recruit the MRE11-RAD50-NBS1 (MRN) complex to DSB sites, enabling end resection by MRE11 and its cofactor CtIP, which generates 3' single-stranded DNA tails essential for strand invasion and repair fidelity. Association of CtIP with PAR further coordinates resection. Inhibition of PARP1 disrupts this process, sensitizing HR-deficient cells to DNA damage through , where unrepaired DSBs accumulate and trigger . Experimental evidence shows that PARP1 depletion significantly reduces MMEJ efficiency in various cell lines, underscoring its critical function in alt-EJ. Recent studies have revealed PARP1's integration into deubiquitination-PARylation feedback loops for DSB signaling, exemplified by the USP10-PARP1 axis. USP10 deubiquitinates PARP1, enhancing its PARylation activity and recruitment of repair factors, while PARylated PARP1 stabilizes USP10, forming a positive loop that amplifies DSB response and repair. This mechanism, identified in 2025 research, promotes efficient DNA damage resolution but also influences sensitivity to in therapeutic contexts.

Involvement in Cellular Signaling

Transcriptional Regulation and Chromatin Dynamics

PARP1 plays a pivotal role in by catalyzing the poly(ADP-ribosyl)ation (PARylation) of core histones, which alters architecture to facilitate . Specifically, PARP1 PARylates at promoter regions, leading to its eviction and subsequent decondensation of , thereby enhancing accessibility for transcription factors and (Pol II) at genes such as CCND1 and Dcx https://pmc.ncbi.nlm.nih.gov/articles/PMC9454564/. Similarly, PARylation of histone H2B, particularly at glutamate residue 35, reduces H2B occupancy at specific promoters like NFATc1 and modulates events to influence adipogenic , promoting a more open state conducive to transcription https://pmc.ncbi.nlm.nih.gov/articles/PMC9454564/. These modifications occur independently of DNA damage signals, enabling PARP1 to fine-tune dynamics during basal and stimulated transcription https://www.pnas.org/doi/10.1073/pnas.1405005111. Beyond histone modifications, PARP1 directly influences Pol II processivity to control gene activation and repression. As a co-activator, PARP1 interacts with the transcription factor to enhance expression of a subset of its target genes, such as those involved in , by binding to promoters and promoting relaxation https://pmc.ncbi.nlm.nih.gov/articles/PMC7856298/. Conversely, PARP1 can repress transcription by stalling Pol II through association with the negative elongation factor (NELF) complex on nascent ; subsequent PARylation of NELF-E disrupts this interaction, releasing Pol II for elongation and activating productive transcription at select loci https://www.science.org/doi/10.1126/science.aaf7865. This dual mechanism allows PARP1 to regulate Pol II pausing index and co-transcriptional splicing, as evidenced in studies showing altered Pol II kinetics upon PARP1 binding to nucleosomes https://www.sciencedirect.com/science/article/pii/S1097276522001599. In the Wnt/β-catenin signaling pathway, PARP1 exerts tankyrase-independent effects by serving as a co-activator for the TCF-4/β-catenin complex, enhancing transcription of Wnt target genes in contexts like APC-deficient https://www.nature.com/articles/s41421-021-00323-9. This role involves PARP1's recruitment to promoters without reliance on AXIN degradation, distinguishing it from tankyrase-mediated PARylation of AXIN, and supports β-catenin stabilization for pathway activation https://www.nature.com/articles/s41421-021-00323-9. Research has shown PARP1's involvement in biomolecular , forming condensates that organize transcriptional hubs. PARP1-driven PARylation disrupts phase-separated condensates of positive transcription b (P-TEFb), inhibiting global transcription in response to stress while concentrating regulatory factors at specific loci for targeted https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-025-02428-1. These dynamic assemblies enhance the efficiency of transcriptional machinery assembly, bridging with gene-specific regulation https://www.cell.com/trends/biochemical-sciences/fulltext/S0968-0004(24)00304-9. As of 2025, advances in detecting serine-specific have further clarified PARP1's roles in these processes https://www.nature.com/articles/s41589-025-01974-5.

Inflammation and Immune Response Modulation

PARP1 plays a pivotal role in inflammatory signaling by promoting the activation of the , a key regulator of . Through its catalytic activity, PARP1 directly interacts with subunits p50 and p65, facilitating their nuclear translocation and transcriptional enhancement, which in turn drives the expression of pro-inflammatory cytokines such as TNF-α and IL-6. This process is mediated by PARP1's PARylation of -associated proteins, including the subunit p65/, thereby amplifying inflammatory gene transcription in immune cells like macrophages and dendritic cells. In the context of immune-specific pathways, this mechanism contrasts with broader transcriptional co-activation roles by specifically targeting networks involved in acute inflammatory responses. In macrophages, PARP1 influences polarization toward a pro-inflammatory M1 phenotype, particularly under conditions of . Activation of PARP1 by (ROS) triggers PARylation events that upregulate inflammatory mediators and sustain ROS production, thereby reinforcing the inflammatory milieu. For instance, PARP1 interacts with LSD1 to control the transcription of (), enabling M1 macrophages to withstand hydrogen peroxide-induced while maintaining their cytokine-secreting capacity. This ROS-mediated loop positions PARP1 as a central modulator of macrophage-driven , distinct from its general functions. Genetic and pharmacological inhibition of PARP1 has consistently shown protective effects against excessive in preclinical models. In , PARP1 mice exhibit reduced systemic production, attenuated signaling, and improved survival rates compared to wild-type controls, highlighting PARP1's contribution to inflammatory amplification during infection. Similarly, in experimental models such as collagen-induced arthritis, PARP1 deficiency leads to decreased , lower expression of pro-inflammatory mediators, and partial amelioration of severity, underscoring its role in chronic immune dysregulation. Recent investigations have extended PARP1's immune modulatory functions to antiviral responses, where its PARylation activity targets signal transducer and activator of transcription (STAT) proteins. Specifically, PARP1-mediated of STAT1α enhances its enhancer-binding capacity in response to interferon-γ, promoting the transcription of antiviral genes and bolstering innate immune defenses against viral pathogens. This mechanism, elucidated in studies around but further contextualized in ongoing research, illustrates PARP1's nuanced role in fine-tuning immune signaling beyond inflammation pathways.

Role in Cell Fate and Aging

Programmed Cell Death Pathways

PARP1 plays a dual role in programmed cell death pathways, promoting cell survival through DNA repair under moderate stress but triggering death mechanisms upon hyperactivation in response to severe DNA damage. In low to moderate damage scenarios, PARP1 facilitates base excision repair and other pathways to maintain genomic integrity and promote survival, whereas extensive damage leads to its prolonged activation, shifting toward cell death execution. A primary pathway mediated by PARP1 is parthanatos, a caspase-independent form of characterized by hyperactivation of PARP1 following massive DNA strand breaks, resulting in rapid depletion of NAD+ and subsequent ATP exhaustion. This NAD+ consumption impairs cellular energy production, while the synthesized poly(ADP-ribose) (PAR) polymers directly bind to apoptosis-inducing factor (AIF) in the mitochondria, inducing its release and nuclear translocation, where AIF executes large-scale DNA fragmentation and chromatin condensation. The PAR-AIF interaction facilitates mitochondrial outer membrane permeabilization (MOMP), amplifying the caspase-independent death signal without involving classical apoptotic . This context-dependent switch underscores PARP1's role as a molecular rheostat: moderate supports repair and survival, but hyperactivation commits cells to parthanatos as an altruistic mechanism to eliminate irreparably damaged cells and prevent . Recent studies have further implicated PARP1 in , an iron-dependent regulated cell death driven by , where PARP1 inhibition sensitizes BRCA1-deficient cells to ferroptosis by downregulating GPX4-mediated protection against phospholipid peroxidation. In this pathway, PARP1 activity appears to regulate lipid peroxidation thresholds, linking DNA damage responses to oxidative demise in specific cellular contexts.

Contribution to Cellular Senescence and Aging

PARP1-mediated poly(ADP-ribosyl)ation (PARylation) accumulates in senescent cells, contributing to a persistent DNA damage response (DDR) that reinforces cellular arrest. Senescent cells exhibit elevated baseline levels of PARP1 expression and PARylation compared to non-senescent counterparts, which sustains DDR signaling and promotes the senescence-associated secretory phenotype (SASP). This hyperactivation of PARP1 in response to unresolved DNA lesions, such as those from oxidative stress or replication fork stalling, depletes cellular NAD+ pools, impairing energy metabolism and amplifying inflammatory signals via NF-κB coactivation. Consequently, the persistent DDR driven by PARP1 not only halts proliferation to prevent tumorigenesis but also exacerbates tissue dysfunction in aging organisms. PARP1 plays a critical role in telomere maintenance, where its dysregulation accelerates shortening and triggers replicative , partly through impairment of (HR). Under chronic , PARP1 activation promotes telomere attrition by enhancing inflammatory pathways like , leading to accelerated shortening in human fibroblasts—up to 1938 base pairs over 45 population doublings compared to 1490 without stress. PARP1 interacts with telomeric proteins such as TRF1 and TRF2, facilitating replication and repair at ends; however, excessive PARylation disrupts HR by sequestering repair factors and depleting NAD+, which limits ATP availability for recombination processes. This HR impairment exacerbates uncapped telomeres, activating a p53-dependent program that limits replicative potential in aging cells. In longevity studies, caloric restriction (CR) mitigates PARP1 hyperactivity, preserving NAD+ for activation and extending lifespan in model organisms. CR, involving a 20-40% reduction in caloric intake, lowers PARP1 activity by reducing oxidative DNA damage and , thereby mimicking the benefits of PARP1 inhibition, such as enhanced mitochondrial function and delayed . In Caenorhabditis elegans, PARP1 inhibition rescues shortened lifespan under hyperglycemic stress by improving insulin signaling and metabolic resilience, while in Drosophila, muscle-specific PARP1 knockdown extends lifespan via AMPKα-mediated . These effects highlight PARP1's dual role: moderate activity supports genomic stability for , but chronic hyperactivation accelerates aging, whereas balanced reduction through CR promotes healthspan. Recent investigations reveal that catalytically inactive PARP1 states contribute to age-related genomic through dominant-negative mechanisms. Expression of inactive PARP1 (e.g., E988A ) in heterozygous mice leads to embryonic by E9.5, with a 5.5-fold increase in sister chromatid exchanges and elevated mitotic errors due to persistent binding at DNA damage sites, blocking repair pathways like . Although primarily studied in development, this accumulation of non-functional PARP1 in aging tissues could similarly impair DDR resolution, fostering chromosomal aberrations and akin to PARP1 deficiency models that shorten mean lifespan by approximately 13%. Such findings underscore PARP1's structural role beyond in maintaining genomic integrity during aging.

Implications in Human Disease

Overexpression and Dysregulation in Cancer

PARP1 is frequently upregulated in various human cancers, with studies indicating overexpression in approximately 70% of primary adenocarcinomas and elevated mRNA levels compared to normal tissues in , ovarian, , , and other malignancies. This upregulation occurs through mechanisms such as epigenetic derepression, where altered and modifications enhance PARP1 transcription, and , particularly noted in , , and ovarian cancers. Hyperactive PARP1 contributes to oncogenesis by promoting error-prone pathways, independent of BRCA status. A key consequence of PARP1 overexpression is the enhancement of alternative end-joining (alt-EJ) and microhomology-mediated end joining (MMEJ) pathways, which lead to mutagenic repairs and increased genomic instability. PARP1 facilitates these processes by recruiting DNA polymerase θ (Pol θ) to DNA breaks, resulting in deletions and insertions that accumulate mutations and drive tumor evolution. In breast and colorectal cancers, this PARP1-dependent alt-EJ activity has been shown to sustain proliferative signaling and metastatic potential by perpetuating chromosomal aberrations. Elevated PARP1 levels are strongly associated with adverse clinical outcomes, including poor overall survival and resistance to . In early-stage , nuclear PARP1 overexpression correlates with reduced survival rates and higher tumor aggressiveness, particularly in triple-negative subtypes. Similarly, in epithelial , high PARP1 expression predicts resistance and worse . This resistance arises from PARP1's role in bolstering and anti-apoptotic pathways, allowing cancer cells to evade treatment-induced damage. Recent analyses highlight PARP1's involvement in remodeling the through inflammatory signaling, as detailed in 2024 reviews. Overexpressed PARP1 activates pathways, leading to the production of pro-inflammatory cytokines such as TNFα and IL-6, which foster an immunosuppressive niche that supports tumor growth and immune evasion. In solid tumors like , this inflammation-driven remodeling enhances and recruitment of myeloid-derived suppressor cells, further promoting oncogenesis.

Interactions with BRCA1 and BRCA2 in Genomic Instability

PARP1 plays a critical role in the initial response to double-strand breaks (DSBs) by synthesizing poly(ADP-ribose) (PAR) chains, which serve as a scaffold for recruiting repair factors, including the complex. Specifically, PARylation facilitates the binding of RAP80 to PAR-modified , enabling the ubiquitin-dependent recruitment of the -A complex to DSB sites for subsequent (HR) repair. This early PARP1-mediated signaling ensures efficient accumulation, promoting end resection and HR pathway activation. In parallel, functions downstream by loading RAD51 recombinase onto resected single-stranded DNA, a process indirectly supported by PARP1's role in stabilizing repair foci and preventing excessive resection. Disruption of PARP1 activity impairs this coordinated recruitment, leading to delayed / engagement and heightened genomic instability. The functional interplay between PARP1 and /2 is exemplified by , where simultaneous loss of PARP1 function and BRCA1/2 deficiency results in catastrophic genomic collapse. In BRCA-proficient cells, PARP1 handles single-strand break repair via ; however, PARP inhibition in BRCA1/2-mutant cells allows unrepaired single-strand breaks to persist and convert into DSBs during S-phase replication. These replication-associated DSBs cannot be accurately repaired due to HR deficiency, causing fork collapse, chromosomal aberrations, and . This , first demonstrated in BRCA2-deficient models, has been validated across BRCA1/2 mutants, underscoring PARP1's essential backup role in maintaining replication fidelity when HR is compromised. Clinically, germline /2 mutations occur in approximately 0.2-0.3% of the general population (about 1 in 400 individuals), conferring elevated risks of , ovarian, and other cancers. These mutations define a "BRCAness" phenotype in tumors, characterized by HR deficiency and to PARP1 inhibition, enabling targeted therapies that exploit for selective tumor cell killing while sparing normal cells. Tumors exhibiting BRCAness, even without direct BRCA mutations, respond similarly, broadening therapeutic applicability. Recent studies have elucidated that PARP1 trapping on DNA—where inhibitors stabilize PARP1-DNA complexes—amplifies lethality in BRCA-deficient cells beyond mere catalytic inhibition. In 2023 research, compounds like nimbolide were shown to induce PARP1 trapping by targeting RNF114, a ubiquitin ligase that modulates PARP1 release, resulting in persistent DNA damage and enhanced cell death in HR-deficient models resistant to standard PARP inhibitors. Similarly, investigations into PARylation dynamics revealed that BRCA1 PARylation by PARP1 restricts excessive resection, and its inhibition promotes over-resection via the BRCA2/EXO1 axis, further sensitizing BRCA-mutant cells to trapping-induced toxicity. These findings highlight trapping as a dominant mechanism driving synthetic lethality, informing next-generation inhibitor designs.

Therapeutic Applications

PARP Inhibitors in Cancer Treatment

PARP inhibitors (PARPi) represent a cornerstone in the targeted therapy of cancers harboring defects in homologous recombination repair, particularly those with BRCA1/2 mutations. The U.S. Food and Drug Administration (FDA) first approved olaparib in December 2014 for the maintenance treatment of patients with deleterious or suspected deleterious germline BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. Subsequent approvals expanded its use to BRCA-mutated breast cancer and other indications. Talazoparib received FDA approval in October 2018 for the treatment of adults with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer. Other approved PARPi, such as niraparib and rucaparib, have also demonstrated progression-free survival benefits in maintenance therapy for recurrent ovarian cancer. These agents exploit synthetic lethality in BRCA-deficient tumors by inhibiting PARP1's catalytic activity, which prevents the repair of single-strand DNA breaks, and by promoting PARP1-DNA trapping, where the inhibitor-bound PARP1 remains anchored to DNA damage sites, exacerbating replication fork collapse and cell death. This dual mechanism underlies their efficacy in ovarian and breast cancers with BRCA alterations. Clinical trials have demonstrated significant improvements in progression-free survival (PFS) with PARPi in BRCA-mutated cancers. For instance, in patients with BRCA-mutated advanced ovarian cancer, maintenance therapy with olaparib extended median PFS by 7 to 14 months compared to placebo in phase III trials, with similar benefits observed in BRCA-mutated breast cancer cohorts treated with talazoparib. These gains are attributed to the selective vulnerability of HR-deficient cells to unrepaired DNA damage, a form of synthetic lethality arising from impaired double-strand break repair. However, resistance frequently emerges through reversion mutations that restore BRCA1/2 functionality, allowing tumor cells to regain homologous recombination proficiency and evade PARPi-induced lethality; such mutations have been detected in 0–21% of resistant ovarian cancer cases and up to 40–50% of breast cancer cases post-PARPi exposure. Other resistance pathways include upregulated alternative DNA repair mechanisms, contributing to disease progression despite initial responses. As of 2025, advances in PARPi development focus on selective PARP1 inhibitors to enhance therapeutic indices by minimizing off-target effects on PARP2 and reducing hematologic toxicities. AZD5305 (saruparib), a highly selective PARP1 inhibitor, is under evaluation in phase II trials such as PETRANHA for metastatic , showing promising antitumor activity and manageable safety when combined with pathway inhibitors, with preliminary data indicating high response rates in HR-deficient subsets. strategies are also advancing, pairing PARPi with to leverage increased and neoantigen release for enhanced T-cell infiltration, as seen in ongoing trials of plus PD-1 inhibitors in BRCA-mutated solid tumors. Additionally, synergies with DNA-damaging agents like amplify in resistant or HR-proficient cancers by overwhelming repair pathways. These approaches aim to broaden PARPi utility beyond monotherapy while addressing resistance challenges.

Emerging Roles in Neurodegeneration and Other Diseases

In neurodegenerative diseases such as (AD), hyperactivation of PARP1 by amyloid-β aggregates triggers and DNA damage, leading to astrocytic metabolic failure and subsequent neuronal death through mechanisms including parthanatos. Similarly, in (PD), pathologic α-synuclein fibrils induce PARP1 activation, resulting in poly(ADP-ribose) polymer formation that feeds forward α-synuclein aggregation and drives neuronal loss via parthanatos. Preclinical studies have demonstrated that , such as veliparib, provide by mitigating amyloid-β-induced toxicity and α-synuclein-mediated in AD and PD models, respectively, highlighting their potential to preserve neuronal function. Beyond neurodegeneration, PARP1 plays a critical role in cardiovascular pathologies, particularly ischemia-reperfusion injury, where its hyperactivation in response to oxidative DNA damage depletes cellular NAD+ levels, impairs mitochondrial function, and exacerbates cardiomyocyte death. This NAD+ exhaustion disrupts and promotes , contributing to and progression. Studies have shown PARP1's involvement in autoimmune diseases, including systemic lupus erythematosus (SLE), where elevated PARP1 activity correlates with dysregulated DNA repair and heightened inflammatory responses in immune cells. In SLE, PARP1 polymorphisms and increased poly(ADP-ribose) polymerase activity are associated with disease susceptibility and autoantibody production, suggesting a role in perpetuating chronic inflammation. For metabolic disorders like type 2 diabetes, PARP1 activation links oxidative stress to inflammatory cascades, promoting insulin resistance and complications such as diabetic retinopathy through elevated poly(ADP-ribose) levels and cytokine release. A 2024 study further confirmed that PAR levels mediate reactive oxygen species-induced inflammation in diabetic patients, positioning PARP1 as a key modulator of metabolic dysfunction. PARP inhibitors are advancing in clinical trials for non-oncologic applications, including preclinical and early-phase studies for , where they target PARP1 to reduce ischemia-reperfusion damage and . In (ALS), preclinical studies suggest PARP inhibitors may halt degeneration by mitigating PARP1 overactivation. These developments build on PARP1's established links to pathways, offering hope for disease-modifying therapies in these conditions.

Protein Interactions and Regulation

Key Protein-Protein Interactions

PARP1, a central in DNA damage response and chromatin dynamics, forms direct and indirect interactions with numerous proteins to orchestrate cellular responses. One of its core binding partners is XRCC1, a in (BER) that binds PARP1 through its poly(ADP-ribose) (PAR) chains, with a dissociation constant (Kd) in the nanomolar range for PAR-modified PARP1, enabling recruitment of β and ligase III to single-strand breaks. Similarly, PARP1 interacts with 53BP1, a key mediator in double-strand break (DSB) signaling, where PARP1's PARylation modulates 53BP1 accumulation at damage sites to influence non-homologous end-joining pathway choice. Another prominent interactor is , the tumor suppressor protein, with which PARP1 forms a complex that enhances p53's transcriptional activity on pro-apoptotic genes, though PARylation of p53 can also attenuate its function in certain stress contexts. PARP1 also binds high-mobility group box 1 (), a architectural protein, to facilitate relaxation and access to DNA lesions; this interaction, strengthened by PARylation, promotes HMGB1's role in bending DNA for repair factor assembly. Recent proximity studies have mapped PARP1's interactome, identifying over 500 proximal partners under replication stress conditions, with major hubs in DNA damage response (e.g., , MDC1, RPA complex) and transcription (e.g., SSRP1, FUS). These networks underscore PARP1's role as a signaling hub, where binding affinities often depend on DNA-induced conformational changes and PAR modification, rather than constitutive associations. In non-mammalian organisms, such as , PARP1 homologs exhibit conserved interactions with BER scaffolds analogous to XRCC1 but feature distinct partners, like radical-induced 1 (RCD1), highlighting evolutionary adaptations in stress signaling. PARP1 further references and in , where transient binding supports genomic stability during replication fork repair.

Post-Translational Regulation of PARP1 Activity

PARP1 activity is tightly controlled by various post-translational modifications that modulate its enzymatic function, DNA binding affinity, and protein stability in response to cellular stress and DNA damage. by the DNA damage-responsive kinases and ATR represents a primary activation mechanism following double-strand breaks (DSBs). ATM associates with PARP1 upon DNA damage and phosphorylates it at specific sites, enhancing PARP1's catalytic activity and facilitating efficient PARylation at lesion sites to promote repair signaling. Similarly, ATR phosphorylates PARP1, as seen at Ser179 in contexts like calcium overload-induced stress, where this modification fine-tunes PARP1's response to prevent excessive activity, though in DSB contexts, it generally supports activation for repair initiation. Acetylation of PARP1 by the histone acetyltransferase PCAF also regulates its function, primarily by enhancing its auto- and hetero-modification capabilities. This modification occurs on residues and promotes PARP1's PARylation activity during stress responses, such as mechanical stretch in cardiomyocytes, thereby amplifying downstream signaling for cell survival or pathways. In contrast, deacetylation by sirtuins like SIRT1 counteracts this, reducing PARP1 activity to favor cell survival under . Ubiquitination targets PARP1 for proteasomal degradation, providing a mechanism to limit its accumulation and prevent prolonged signaling. While specific ligases like RNF146 recognize PARylated PARP1 to mediate this degradation via K48-linked chains, recent studies highlight a regulatory loop involving deubiquitination by USP10, which removes from PARP1 at sites like K418, stabilizing the protein and enhancing its PARylation activity in a manner to promote DNA damage repair; this axis is particularly relevant in , where elevated USP10 correlates with PARP1 levels and resistance to inhibitors. Sumoylation of PARP1, primarily at lysine residues in its regulatory domains, is stimulated by DNA binding and serves to modulate its chromatin interactions without significantly disrupting catalytic or DNA-binding properties. This modification, often DNA-dependent, facilitates PARP1's role in transcription and repair by altering its dynamics at damage sites, as evidenced by structural analyses showing minimal conformational impact from SUMO attachment. In some contexts, sumoylation promotes PARP1 dissociation from specific chromatin regions, indirectly fine-tuning its localization. PARP1's macrodomains play a critical role in allosteric regulation by binding poly(ADP-ribose) (PAR) chains, which influences its retention on DNA and overall activity. These domains recognize both self-generated PAR and external chains, transmitting signals that modulate catalytic output; for instance, PAR binding can inhibit further elongation, providing feedback control. PAR glycohydrolase (PARG) counteracts this by rapidly degrading PAR chains, particularly poly-ADP-ribosylated forms on PARP1, allowing enzyme recycling and preventing persistent chromatin trapping, with PARG acting more efficiently on highly modified PARP1 compared to mono-modifiers like MacroD2. This dynamic interplay ensures temporal control of PARP1 function during repair. A key feedback mechanism for PARP1 self-regulation is auto-PARylation, where the enzyme modifies itself on multiple residues, primarily serines in its auto-modification domain, leading to electrostatic repulsion from negatively charged DNA and subsequent release from the damage site. This self-inactivation terminates excessive PARylation, prevents resource depletion of NAD⁺, and allows recruitment of downstream repair factors, with the process being essential for faithful Okazaki fragment processing and overall genome stability.

PARP1 in Non-Mammalian Organisms

Functions in Plant Stress Response and Development

In , PARP1 and PARP2 play crucial roles in abiotic stress responses, particularly in , where they contribute to managing (ROS) accumulation during and salt stress. Unlike in mammals, where PARP activation primarily signals , plant PARP1 and PARP2 exhibit higher basal activity and are activated by environmental cues that induce oxidative damage, leading to poly(ADP-ribosyl)ation (PARylation) that modulates by consuming NAD+. This process helps balance cellular resources, but excessive activation under stress depletes NAD+, exacerbating ROS-induced damage and . Studies show that knockdown or inhibition of PARP1 and PARP2 reduces PARylation, preserves NAD+ levels, and enhances ROS scavenging, thereby improving tolerance to and salt without compromising overall plant vigor. During drought, PARP1 and PARP2 indirectly support stomatal closure by influencing ROS signaling pathways that intersect with (ABA)-mediated responses, promoting adaptive water conservation. In parp1 parp2 double mutants, reduced PARylation leads to lower ROS levels and better maintenance of under , resulting in prolonged survival compared to wild-type plants. Similarly, under salt stress, these enzymes regulate homeostasis and oxidative bursts; their suppression minimizes Na+ toxicity and enhances antioxidant enzyme activity, such as and , for effective ROS detoxification. possesses only three PARP isoforms (PARP1, PARP2, and PARP3) compared to 17 in humans, reflecting a streamlined role in environmental adaptation rather than diverse contexts. In plant development, PARylation by PARP1 and PARP2 influences seed germination and root architecture, integrating stress signals with growth processes. During seed germination, PARylation fine-tunes dormancy release and early establishment; in , PARP1 and PARP2 activity promotes timely seed germination under optimal conditions, while PARP3 supports seed vigor and facilitates germination under mild stress conditions such as oxidative damage, ensuring synchronized emergence. For root growth, PARylation inhibits excessive in meristems; parp1 parp2 mutants exhibit accelerated primary and elongation, enhancing foraging for water and nutrients in nutrient-poor or dry soils. Recent genetic analyses confirm that PARP1 knockouts in model plants like boost stress tolerance—such as to oxidative and challenges—while promoting root expansion without yield penalties under non-stress conditions, highlighting their regulatory balance in development.

Evolutionary Differences from Human PARP1

PARP1 exhibits high evolutionary conservation in its core domains across eukaryotes that possess the gene, with the catalytic domain and domain showing particular stability from early-branching organisms like certain fungi to vertebrates. Phylogenetic analyses have identified PARP1 as part of Clade 1 within the PARP superfamily, featuring the conserved essential for poly(ADP-ribosyl)ation activity linked to functions. This conservation underscores PARP1's ancient role in maintaining genomic integrity, with orthologs in species such as displaying over 50% sequence identity in the catalytic region compared to human PARP1. A major evolutionary divergence arises from events that expanded the PARP family, contrasting the limited repertoire in simpler eukaryotes with the complexity in mammals. While budding yeast like lack any PARP genes, other fungi retain a single PARP ortholog, reflecting secondary loss in some lineages. In contrast, mammals have undergone extensive duplications, resulting in 17 PARP genes, including PARP1, which diversified domain architectures and substrate specificities. These expansions, particularly in metazoans, enabled specialized roles beyond basic . Functional shifts in PARP1 highlight adaptations across taxa, with prioritizing roles in and repair, while mammals incorporate additional signaling in and immunity. In , the single PARP ortholog (dParp) primarily facilitates serine for and replication fork stability during DNA damage response, lacking the broader inflammatory modulation seen in mammals. Human PARP1, through interactions with and other factors, extends to regulating production and immune cell activation, representing a metazoan in stress signaling. Recent phylogenetic studies reinforce PARP1's origin in an ancestral mechanism, with positive selection and duplications driving diversification in metazoans for enhanced signaling capacities.

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC4030864/
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC4806654/
  3. https://www.sciencedirect.com/science/article/pii/S0006295224000285
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC4477203/
  5. https://www.sciencedirect.com/science/article/abs/pii/0006291X87905432
  6. https://omim.org/entry/173870
  7. https://www.ncbi.nlm.nih.gov/gene/142
  8. https://portlandpress.com/biochemj/article/389/2/423/93433/Regulation-of-the-poly-ADP-ribose-polymerase-1
  9. https://www.proteinatlas.org/ENSG00000143799-PARP1/tissue
  10. https://www.sciencedirect.com/science/article/abs/pii/S1357272504003784
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC2964712/
  12. https://www.sciencedirect.com/science/article/abs/pii/S0531556500001340
  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC3060520/
  14. https://pmc.ncbi.nlm.nih.gov/articles/PMC8769213/
  15. https://academic.oup.com/nar/article/47/8/3811/5364136
  16. https://www.uniprot.org/uniprotkb/P09874/entry
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC1952076/
  18. https://www.pnas.org/doi/10.1073/pnas.94.14.7303
  19. https://www.sciencedirect.com/science/article/pii/S1672022916300705
  20. https://www.nature.com/articles/s41388-025-03428-7
  21. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.712556/full
  22. https://genesdev.cshlp.org/content/26/5/417.full
  23. https://www.mdpi.com/2076-0817/12/7/964
  24. https://www.sciencedirect.com/science/article/abs/pii/S0891584918317581
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC8110256/
  26. https://arthritis-research.biomedcentral.com/articles/10.1186/ar1865
  27. https://www.nature.com/articles/s41467-021-24225-2
  28. https://academic.oup.com/nar/article/45/22/12834/4599181
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC9266317/
  30. https://www.molbiolcell.org/doi/10.1091/mbc.E18-10-0650
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC4454457/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC11415882/
  33. https://pubmed.ncbi.nlm.nih.gov/40327273/
  34. https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.15716
  35. https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2023.1202152/full
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC3844163/
  37. https://www.nature.com/articles/s42003-023-04596-6
  38. https://www.aging-us.com/article/100052/text
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC5772855/
  40. https://www.pnas.org/doi/10.1073/pnas.2213857120
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC3459245/
  42. https://www.pnas.org/doi/10.1073/pnas.2301972120
  43. https://pubmed.ncbi.nlm.nih.gov/19415146/
  44. https://www.sciencedirect.com/science/article/pii/S0304419X25000241
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC3092251/
  46. https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.201800092R
  47. https://www.nature.com/articles/s42003-018-0077-8
  48. https://pmc.ncbi.nlm.nih.gov/articles/PMC11192709/
  49. https://www.sciencedirect.com/science/article/pii/S092375341934671X
  50. https://pmc.ncbi.nlm.nih.gov/articles/PMC11275100/
  51. https://www.mdpi.com/1422-0067/25/16/9032
  52. https://www.sciencedirect.com/science/article/pii/S1535610813001323
  53. https://www.sciencedirect.com/science/article/pii/S0093775423000611
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC6591728/
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC3117132/
  56. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet
  57. https://www.jci.org/articles/view/181062
  58. https://www.science.org/doi/10.1126/sciadv.adg7752
  59. https://www.sciencedirect.com/science/article/pii/S2211124723000712
  60. https://www.sciencedirect.com/science/article/pii/S2405803324001341
  61. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2014/lynparza-approved-us-fda-brca-mutated-ovarian-cancer-treatment-19122014.html
  62. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-gbrcam-her2-negative-locally-advanced-or-metastatic-breast-cancer
  63. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-maintenance-treatment-recurrent-epithelial-ovarian-fallopian-tube-or-primary-peritoneal
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC7509090/
  65. https://pmc.ncbi.nlm.nih.gov/articles/PMC8034970/
  66. https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1133472/full
  67. https://www.sciencedirect.com/science/article/pii/S2352304223000661
  68. https://www.annalsofoncology.org/article/S0923-7534%2825%2903920-1/abstract
  69. https://pmc.ncbi.nlm.nih.gov/articles/PMC7352466/
  70. https://www.nature.com/articles/s41416-023-02326-7
  71. https://academic.oup.com/brain/article/134/6/1658/375285
  72. https://www.science.org/doi/10.1126/science.aat8407
  73. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.13748
  74. https://www.nature.com/articles/s41467-019-09014-2
  75. https://biosignaling.biomedcentral.com/articles/10.1186/s12964-024-01903-4
  76. https://pubmed.ncbi.nlm.nih.gov/19376176/
  77. https://academic.oup.com/rheumatology/article/45/6/711/1784932
  78. https://pubs.acs.org/doi/10.1021/acs.jproteome.5c00645
  79. https://pmc.ncbi.nlm.nih.gov/articles/PMC11510672/
  80. https://www.sciencedirect.com/science/article/pii/S2213231724002210
  81. https://www.researchgate.net/publication/353145790_Emerging_role_of_PARP-1_and_PARthanatos_in_ischemic_stroke
  82. https://www.sciencedirect.com/science/article/abs/pii/S1568163723002374
  83. https://www.jbc.org/article/S0021-9258(20)49220-8/fulltext
  84. https://academic.oup.com/nar/article/50/20/11600/6814461
  85. https://pmc.ncbi.nlm.nih.gov/articles/PMC4134958/
  86. https://pmc.ncbi.nlm.nih.gov/articles/PMC2518631/
  87. https://pmc.ncbi.nlm.nih.gov/articles/PMC6479469/
  88. https://www.nature.com/articles/s41467-019-10741-9
  89. https://bmcmolbiol.biomedcentral.com/articles/10.1186/1471-2199-8-29
  90. https://pmc.ncbi.nlm.nih.gov/articles/PMC8252533/
  91. https://www.nature.com/articles/s41467-017-01807-7
  92. https://pubmed.ncbi.nlm.nih.gov/40316740/
  93. https://pubmed.ncbi.nlm.nih.gov/23871147/
  94. https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.09-137695
  95. https://pmc.ncbi.nlm.nih.gov/articles/PMC7097781/
  96. https://www.cell.com/molecular-cell/fulltext/S1097-2765%2825%2900747-6
  97. https://onlinelibrary.wiley.com/doi/10.1111/j.1365-313X.2004.02277.x
  98. https://www.mdpi.com/1422-0067/20/7/1638
  99. https://pmc.ncbi.nlm.nih.gov/articles/PMC5292411/
  100. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0037287
  101. https://doi.org/10.1007/s11103-015-0363-5
  102. https://www.mdpi.com/2311-7524/8/1/78
  103. https://www.nature.com/articles/s41598-020-78116-5
  104. https://www.nature.com/articles/s41467-023-38793-y
  105. https://pubmed.ncbi.nlm.nih.gov/17981777/
  106. https://www.biorxiv.org/content/10.1101/2024.09.19.613696v1.full-text
Add your contribution
Related Hubs
User Avatar
No comments yet.