Biology:BRIP1

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] Damage or depletion of BRIP1 has been associated with various cancers as well as Fanconi anemia.[2][3]

Function

Cell Cycle

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.[2] 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.[2]

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.[2][4][5] Like the ATPase activity, this interaction depends on phosphorylation at Ser-990. This interaction is also required for IR-induced arrest at G2-M.[2]

DNA Repair

BRIP1 protein is a DNA helicase that is employed in homologous recombinational repair, and in the response of the cell to DNA replication stress.[6] In part, BRIP1 carries out its function through interaction with other key DNA repair proteins, specifically MLH1, BRCA1 and BLM.[6] 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.[2][7] BRIP1 can however also bind to 5’ flap, D-loop and guanine quadruplex (G4) structures.[7] 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.[2]

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.[2][8] It has been observed that DSB repair is delayed in cells with depleted or damaged BRIP1.[2] BRIP1 additionally helps recruit CtIP to DSB break sections, and helps ensure proper 5’ end resection.[8] BRIP1 may be a target of germline cancer-inducing mutations.[9]

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.[2] 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.[10] A deficiency of BRIP1 causes increased DNA damage, mitochondrial abnormalities and neuronal cell death.

Meiosis

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.[11] 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.[11]

The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations.[9]

Structure

BRIP1 is a 1249 residue polypeptide and a member of the DEAH family of helicases, as characterized by seven motifs in its structure common to this family (I, Ia, II, III, IV, V, VI) [5]. Like other members of this family, it moves continuously along DNA and removes strands and proteins in its path. It also contains a nuclear localization signal from positions 158-175, and an Fe-S domain between helicase motifs Ia and II, which is essential for helicase activity.[2]

BRIP1 has several different domains for interacting with BRCA1, and MutL𝛼, as well as ATP and DNA substrates. An 888-residue structure at the N-terminus makes up the ATPase and helicase domain, which encapsulates all aforementioned motifs. The BRCA1 binding site sits outside this domain in the C-terminus between residues 976-1006. It includes a S-X-X-F motif required for interaction with BRCA1. Two MutL𝛼 interaction domains are within the helicase domain - one between motifs II and III and another between motifs V and VI.[2]

Several important amino acids have been identified in BRIP1. The lysine at position 52 is required for hydrolyzing ATP, and is conserved across many ATPases and helicases. The proline at position 47 (P47) and the methionine at position 299 (M299) are both important for ATPase activity, with P47 also impacting helicase activity and overall enzyme stability. A mutation at P47 diminishes stability and activity as both an ATPase and helicase, while a M299I mutation appears to increase ATPase activity. MLH1 interaction is enabled by lysines at 141 and 142, and BRCA1 interaction is enabled by P991 and F993 in addition to phosphorylation at S990.[2]

Mutations in BRIP1 have been linked to breast cancer, Fanconi anemia, and ovarian cancer. R251C and Q255H mutations inhibit helicase activity and have been associated with Fanconi anemia, while the M299I has been associated with breast cancer.[3] Additionally, a A349P mutation inhibits the enzyme’s ability to displace proteins from DNA strands, and reduces resistance to DNA damage.[3] Mutations in BRIP1 are associated with a 10-15% risk of ovarian cancer.[12]

BRIP1 proteins in different animals vary in homology to human BRIP1. Proteins isolated from chickens and nematodes (54% and 31% homology to human BRIP1 respectively) were both missing the S-X-X-F motif required for BRCA1 interaction. As such, BRIP1 is unlikely to play a role in BRCA1-dependent DSB repair in these organisms.[2]

Interactions

BRIP1 has been shown to interact with BRCA1.[13][14][15][16][17]

References

  1. ↑ "UniProt" (in en). https://www.uniprot.org/uniprotkb/Q9BX63/entry. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 Ali, Abdullah Mahmood; Singh, Thiyam Ramsing; Meetei, Amom Ruhikanta (2009-07-31). "FANCM–FAAP24 and FANCJ: FA proteins that metabolize DNA". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. Fanconi Anemia: A paradigm of discovering molecular pathways from patients 668 (1): 20–26. doi:10.1016/j.mrfmmm.2009.04.002. ISSN 0027-5107. PMID 19379763. Bibcode: 2009MRFMM.668...20A. 
  3. ↑ 3.0 3.1 3.2 Guo, Manhong; Vidhyasagar, Venkatasubramanian; Talwar, Tanu; Kariem, Ahmad; Wu, Yuliang (2016-10-01). "Mutational analysis of FANCJ helicase". Methods. DNA Helicases 108: 118–129. doi:10.1016/j.ymeth.2016.04.023. ISSN 1046-2023. PMID 27107905. https://www.sciencedirect.com/science/article/pii/S1046202316301025. 
  4. ↑ Bridge, Wendy L.; Vandenberg, Cassandra J.; Franklin, Roger J.; Hiom, Kevin (September 2005). "The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair" (in en). Nature Genetics 37 (9): 953–957. doi:10.1038/ng1627. ISSN 1546-1718. PMID 16116421. https://www.nature.com/articles/ng1627. 
  5. ↑ "Mutations in BRIP1 confer high risk of ovarian cancer". Nature Genetics 43 (11): 1104–1107. October 2011. doi:10.1038/ng.955. PMID 21964575. 
  6. ↑ 6.0 6.1 "FancJ (Brip1) loss-of-function allele results in spermatogonial cell depletion during embryogenesis and altered processing of crossover sites during meiotic prophase I in mice". Chromosoma 125 (2): 237–252. June 2016. doi:10.1007/s00412-015-0549-2. PMID 26490168. 
  7. ↑ 7.0 7.1 Brosh, Robert M.; Cantor, Sharon B. (2014). "Molecular and cellular functions of the FANCJ DNA helicase defective in cancer and in Fanconi anemia". Frontiers in Genetics 5: 372. doi:10.3389/fgene.2014.00372. ISSN 1664-8021. PMID 25374583. 
  8. ↑ 8.0 8.1 Fang, Chenyan; Zhu, Zhoujun; Cao, Jun; Huang, Jun; Xu, Yipeng (2025-07-30). "Comprehensive review on Fanconi anemia: insights into DNA interstrand cross-links, repair pathways, and associated tumors". Orphanet Journal of Rare Diseases 20 (1): 389. doi:10.1186/s13023-025-03896-w. ISSN 1750-1172. PMID 40739565. 
  9. ↑ 9.0 9.1 "Entrez Gene: BRIP1 BRCA1 interacting protein C-terminal helicase 1". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=83990. 
  10. ↑ "A Novel Role for BRIP1/FANCJ in Neuronal Cells Health and in Resolving Oxidative Stress-Induced DNA Lesions". Journal of Alzheimer's Disease 85 (1): 207–221. 2022. doi:10.3233/JAD-215305. PMID 34776453. 
  11. ↑ 11.0 11.1 "The DNA helicase FANCJ (BRIP1) functions in double strand break repair processing, but not crossover formation during prophase I of meiosis in male mice". PLOS Genetics 20 (2): e1011175. 2024. doi:10.1371/journal.pgen.1011175. PMID 38377115. 
  12. ↑ "Current and future role of genetic screening in gynecologic malignancies". American Journal of Obstetrics and Gynecology 217 (5): 512–521. November 2017. doi:10.1016/j.ajog.2017.04.011. PMID 28411145. 
  13. ↑ "Structural basis of BACH1 phosphopeptide recognition by BRCA1 tandem BRCT domains". Structure 12 (7): 1137–1146. July 2004. doi:10.1016/j.str.2004.06.002. PMID 15242590. 
  14. ↑ "Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure". Genes & Development 16 (5): 583–593. March 2002. doi:10.1101/gad.959202. PMID 11877378. 
  15. ↑ "The BRCT domain is a phospho-protein binding domain". Science 302 (5645): 639–642. October 2003. doi:10.1126/science.1088753. PMID 14576433. Bibcode: 2003Sci...302..639Y. 
  16. ↑ "Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains". The Journal of Biological Chemistry 278 (52): 52914–52918. December 2003. doi:10.1074/jbc.C300407200. PMID 14578343. 
  17. ↑ "Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer". Nature Structural & Molecular Biology 11 (6): 512–518. June 2004. doi:10.1038/nsmb775. PMID 15133502. 

Further reading



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