Fanconi anemia group J protein (FANCJ) is a protein that in humans is encoded by the BRCA1-interacting protein 1 (BRIP1) gene. The protein is a 5’-3’ DNA helicase (EC: 5.2.6.3) and ATPase that repairs interstrand crosslinks (ICLs), double-stranded breaks (DSBs) and guanine quadruplexes (G4) through the Fanconi anemia (FA) pathway. Damage or depletion of BRIP1 has been associated with various cancers as well as Fanconi anemia.

The protein encoded by this gene is a member of the RecQ DEAH helicase family. The protein acts as both a 5’-3’ DNA helicase and ATPase. The ATPase functionality of BRIP1 is important for entry into and timely progression through the S phase in the cell cycle. ATPase activity is diminished during the G₁ phase, and is increased during S and G2-M when the protein is phosphorylated at Ser-990. Additionally, depletion of BRIP1 has been observed to delay entry into the S phase.

BRIP1 is also important for the arrest after G2 before mitosis induced by ionizing radiation (IR) - a mechanism often utilized in cancer treatment. In cells where BRIP1 is depleted or damaged, cells do not arrest after G2 and instead progress into mitosis. BRIP1 also interacts with breast cancer type 1 susceptibility protein (BRCA1), a tumor suppressor, by binding to the C terminus between repeats in the BRCT domain. Like the ATPase activity, this interaction depends on phosphorylation at Ser-990. This interaction is also required for IR-induced arrest at G2-M.

BRIP1 protein is a DNA helicase that is employed in homologous recombinational repair, and in the response of the cell to DNA replication stress. In part, BRIP1 carries out its function through interaction with other key DNA repair proteins, specifically MLH1, BRCA1 and BLM. This group of proteins helps to ensuring genome stability, and in particular repairs DNA double-strand breaks during prophase 1 of meiosis.

5’-3’ DNA-helicase activity in BRIP1 is dependent on its ATPase activity. BRIP1 preferentially binds to DNA at forked duplexes, and can unwind duplexes with 5’ tails of at least 15 nucleotides. BRIP1 can however also bind to 5’ flap, D-loop and guanine quadruplex (G4) structures. Functionality as a DNA-helicase allows BRIP1 to repair interstrand crosslinks (ICLs) via the Fanconi Anemia (FA) pathway. As such, cells without BRIP1 have increased sensitivity to ICL inducing agents. If not repaired, ICLs can lead to a stall in the replication fork. The ability of BRIP1 to repair ICLs is dependent not on BRCA1, but interaction with MLH1, however the exact nature of this dependence is uncertain. Furthermore, it is unclear the exact role BRIP1 plays in ICL repair.

In mammals, BRIP1 is also thought to play a role in the repair of double-stranded breaks (DSBs) in DNA through interaction with BRCA1, which plays a major role in DSB repair. It has been observed that DSB repair is delayed in cells with depleted or damaged BRIP1. BRIP1 additionally helps recruit CtIP to DSB break sections, and helps ensure proper 5’ end resection. BRIP1 may be a target of germline cancer-inducing mutations.

BRIP1 plays a role in the repair of G4 structures in DNA, which can lead to deletions when not repaired. BRIP1 hydrolyzes ATP to unwind these complexes - a process that appears to be unrelated to its function in the FA pathway. BRIP1 appears to have an important role in neuronal cells by suppressing oxidative stress, excitotoxicity induced DNA damage, and in protecting the integrity of mitochondria. A deficiency of BRIP1 causes increased DNA damage, mitochondrial abnormalities and neuronal cell death.

During prophase I of meiosis in male mice, BRIP1 functions in the repair of DNA double-strand breaks, but does not appear to have a role in the formation of chromosomal crossovers. BRIP1 co-localizes with TOPBP1 scaffold protein and the BRCA1 repair protein along chromosome cores starting early in meiotic prophase I forming discrete foci, and is also densely localized to the axes of unsynapsed chromosomes during the late zygonema (zygotene) stage of meiosis.