# BRIP1

## Overview
BRIP1, or BRCA1 interacting protein C-terminal helicase 1, is a gene that encodes a DNA helicase involved in critical DNA repair processes. The protein product, BRCA1 interacting helicase 1, is a member of the DNA helicase family, characterized by its ability to unwind DNA strands, a function essential for maintaining genomic stability. This helicase is particularly significant in the homologous recombination repair pathway, where it interacts with the BRCA1 protein to facilitate the repair of DNA double-strand breaks. The BRIP1 protein contains several functional domains, including a helicase domain and a BRCA1-binding domain, which are crucial for its role in DNA repair and its interaction with other proteins involved in genomic maintenance. Mutations in the BRIP1 gene can lead to impaired DNA repair mechanisms, contributing to genomic instability and an increased risk of cancer, underscoring its role as a tumor suppressor (Calvo2021Comprehensive; Brosh2014Molecular; De2008A).

## Structure
The BRIP1 gene encodes a DNA helicase involved in DNA repair processes, specifically interacting with BRCA1. The protein is composed of 1249 amino acids and contains several key domains essential for its function. The helicase domain, which spans the first 860 amino acids, is crucial for its DNA unwinding activity and resistance to interstrand cross-linking agents like cisplatin (Calvo2021Comprehensive). This domain includes motifs such as the Walker A and B boxes and an iron-sulfur (FeS) cluster, which are vital for its catalytic activity (Calvo2021Comprehensive).

The BRIP1 protein also features a BRCA1-binding domain, which is important for its interaction with BRCA1 and BARD1, another protein involved in DNA repair (Thanassoulas2010Thermodynamic; De2008A). Mutations affecting this domain can lead to impaired protein stability and function, as seen in certain breast cancer-associated mutations (De2008A).

Post-translational modifications, such as phosphorylation, play a role in modulating BRIP1's activity and interactions with other proteins (Calvo2021Comprehensive). The protein may also exist in different splice variant isoforms, which can result in proteins with varying functional properties. These structural features underscore BRIP1's role in maintaining genomic stability and its potential involvement in cancer predisposition.

## Function
The BRIP1 gene encodes a DNA helicase that plays a crucial role in maintaining genomic stability in healthy human cells. This protein is involved in the DNA damage response and repair, particularly through its interaction with the BRCA1 gene product. BRIP1 is essential for promoting error-free DNA repair and is a key component of the homologous recombination repair pathway, which is vital for repairing DNA double-strand breaks (Cantor2011Hereditary; Levran2005The).

BRIP1 functions as a DNA-dependent ATPase and helicase, unwinding DNA strands to facilitate repair processes. It is active in the nucleus, where it interacts with other proteins such as BRCA1, RPA, and MLH1 to localize to DNA damage sites and facilitate repair (Brosh2014Molecular). The helicase activity of BRIP1 is crucial for resolving G-quadruplex DNA structures, which can impede replication and transcription, thereby ensuring smooth replication fork progression and maintaining chromatin structure and epigenetic stability (Brosh2014Molecular).

Mutations in BRIP1 can impair its helicase activity, leading to genomic instability and an increased risk of cancer, highlighting its role as a tumor suppressor gene (Brosh2014Molecular).

## Clinical Significance
Mutations in the BRIP1 gene are associated with an increased risk of several cancers, particularly breast and ovarian cancer. Germline mutations in BRIP1 can lead to a modest increase in breast cancer risk, especially in families without BRCA1/BRCA2 mutations (De2008A). These mutations often result in a truncated protein that disrupts the BRCA1-binding domain, impairing DNA repair processes (De2008A). In ovarian cancer, BRIP1 mutations are linked to a higher risk of epithelial ovarian cancer, particularly the high-grade serous subtype, due to the loss of interaction with BRCA1, which is crucial for DNA damage response (Ramus2015Germline).

BRIP1 is also implicated in Fanconi anemia, a disorder characterized by congenital abnormalities, bone marrow failure, and cancer susceptibility. Biallelic truncating mutations in BRIP1 lead to Fanconi anemia group J, while monoallelic mutations increase cancer susceptibility (Kamal2020Helicaseinactivating). The BRIP1 p.R848H mutation, for instance, is pathogenic for Fanconi anemia in homozygotes and increases cancer risk in heterozygous carriers (Kamal2020Helicaseinactivating).

Alterations in BRIP1 expression and interactions can disrupt DNA repair mechanisms, contributing to genomic instability and cancer development (Wang2023Multimolecular). These findings highlight the clinical significance of BRIP1 mutations in cancer risk assessment and potential therapeutic targeting.

## Interactions
BRIP1, also known as BRCA1 interacting helicase 1, is involved in several critical protein interactions that facilitate its role in DNA repair processes. It interacts with BRCA1, forming a complex that is essential for homologous recombination repair of DNA double-strand breaks (Rizeq2020Novel; Levran2005The). BRIP1 also interacts with replication protein A (RPA), a single-stranded DNA-binding protein, which enhances its helicase activity, particularly in unwinding short DNA duplexes (Gupta2007FANCJ). This interaction is specific and remains intact even in Fanconi Anemia mutant cells, indicating its independence from some FA pathway components (Gupta2007FANCJ).

BRIP1 is part of a network with other genome maintenance genes, including ATM/ATR and the NMR complex genes, and is involved in homology-directed DNA repair (Levran2005The). It also forms DNA damage-inducible foci with RPA, suggesting its involvement in various DNA repair pathways, including interstrand cross-link repair and double-strand break repair (Gupta2007FANCJ). Additionally, BRIP1 interacts with Wwox, a protein that regulates the timing of BRIP1's interactions with the BRCA1-BRCT domain, influencing DNA repair pathway choice (Park2022Wwox).


## References


[1. (Calvo2021Comprehensive) Jennifer A. Calvo, Briana Fritchman, Desiree Hernandez, Nicole S. Persky, Cory M. Johannessen, Federica Piccioni, Brian A. Kelch, and Sharon B. Cantor. Comprehensive mutational analysis of the brca1-associated dna helicase and tumor-suppressor fancj/bach1/brip1. Molecular Cancer Research, 19(6):1015–1025, February 2021. URL: http://dx.doi.org/10.1158/1541-7786.MCR-20-0828, doi:10.1158/1541-7786.mcr-20-0828. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.1158/1541-7786.MCR-20-0828)

[2. (Rizeq2020Novel) Balsam Rizeq, Saïd Sif, Gheyath K. Nasrallah, and Allal Ouhtit. Novel role of brca1 interacting c‐terminal helicase 1 (brip1) in breast tumour cell invasion. Journal of Cellular and Molecular Medicine, 24(19):11477–11488, September 2020. URL: http://dx.doi.org/10.1111/jcmm.15761, doi:10.1111/jcmm.15761. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/jcmm.15761)

[3. (Levran2005The) Orna Levran, Claire Attwooll, Rashida T Henry, Kelly L Milton, Kornelia Neveling, Paula Rio, Sat Dev Batish, Reinhard Kalb, Eunike Velleuer, Sandra Barral, Jurg Ott, John Petrini, Detlev Schindler, Helmut Hanenberg, and Arleen D Auerbach. The brca1-interacting helicase brip1 is deficient in fanconi anemia. Nature Genetics, 37(9):931–933, August 2005. URL: http://dx.doi.org/10.1038/ng1624, doi:10.1038/ng1624. This article has 284 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ng1624)

[4. (Park2022Wwox) Dongju Park, Mehdi Gharghabi, Colleen R. Reczek, Rebecca Plow, Charles Yungvirt, C. Marcelo Aldaz, and Kay Huebner. Wwox binding to the murine brca1-brct domain regulates timing of brip1 and ctip phospho-protein interactions with this domain at dna double-strand breaks, and repair pathway choice. International Journal of Molecular Sciences, 23(7):3729, March 2022. URL: http://dx.doi.org/10.3390/ijms23073729, doi:10.3390/ijms23073729. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms23073729)

[5. (Kamal2020Helicaseinactivating) Lara Kamal, Sarah B. Pierce, Christina Canavati, Amal Abu Rayyan, Tamara Jaraysa, Orit Lobel, Suhair Lolas, Barbara M. Norquist, Grace Rabie, Fouad Zahdeh, Ephrat Levy-Lahad, Mary-Claire King, and Moien N. Kanaan. Helicase-inactivating brip1 mutation yields fanconi anemia with microcephaly and other congenital abnormalities. Molecular Case Studies, 6(5):a005652, October 2020. URL: http://dx.doi.org/10.1101/mcs.a005652, doi:10.1101/mcs.a005652. This article has 3 citations.](https://doi.org/10.1101/mcs.a005652)

[6. (Wang2023Multimolecular) Ruohuang Wang, Jisheng Zhang, Xin Cui, Shun Wang, Ting Chen, Yanfang Niu, Xiaoyun Du, Jingwen Kong, Lin Wang, and Yan Jiang. Multimolecular characteristics and role of brca1 interacting protein c-terminal helicase 1 (brip1) in human tumors: a pan-cancer analysis. World Journal of Surgical Oncology, March 2023. URL: http://dx.doi.org/10.1186/s12957-022-02877-8, doi:10.1186/s12957-022-02877-8. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12957-022-02877-8)

[7. (Brosh2014Molecular) Robert M. Brosh and Sharon B. Cantor. Molecular and cellular functions of the fancj dna helicase defective in cancer and in fanconi anemia. Frontiers in Genetics, October 2014. URL: http://dx.doi.org/10.3389/fgene.2014.00372, doi:10.3389/fgene.2014.00372. This article has 56 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fgene.2014.00372)

[8. (Ramus2015Germline) Susan J. Ramus, Honglin Song, Ed Dicks, Jonathan P. Tyrer, Adam N. Rosenthal, Maria P. Intermaggio, Lindsay Fraser, Aleksandra Gentry-Maharaj, Jane Hayward, Susan Philpott, Christopher Anderson, Christopher K. Edlund, David Conti, Patricia Harrington, Daniel Barrowdale, David D. Bowtell, Kathryn Alsop, Gillian Mitchell, Mine S. Cicek, Julie M. Cunningham, Brooke L. Fridley, Jennifer Alsop, Mercedes Jimenez-Linan, Samantha Poblete, Shashi Lele, Lara Sucheston-Campbell, Kirsten B. Moysich, Weiva Sieh, Valerie McGuire, Jenny Lester, Natalia Bogdanova, Matthias Dürst, Peter Hillemanns, Kunle Odunsi, Alice S. Whittemore, Beth Y Karlan, Thilo Dörk, Ellen L. Goode, Usha Menon, Ian J. Jacobs, Antonis C. Antoniou, Paul D. P. Pharoah, and Simon A. Gayther. Germline mutations in the brip1, bard1, palb2, and nbn genes in women with ovarian cancer. JNCI: Journal of the National Cancer Institute, August 2015. URL: http://dx.doi.org/10.1093/jnci/djv214, doi:10.1093/jnci/djv214. This article has 291 citations.](https://doi.org/10.1093/jnci/djv214)

[9. (Gupta2007FANCJ) Rigu Gupta, Sudha Sharma, Joshua A. Sommers, Mark K. Kenny, Sharon B. Cantor, and Robert M. Brosh. Fancj (bach1) helicase forms dna damage inducible foci with replication protein a and interacts physically and functionally with the single-stranded dna-binding protein. Blood, 110(7):2390–2398, October 2007. URL: http://dx.doi.org/10.1182/blood-2006-11-057273, doi:10.1182/blood-2006-11-057273. This article has 95 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2006-11-057273)

[10. (Cantor2011Hereditary) Sharon B Cantor and Shawna Guillemette. Hereditary breast cancer and the brca1-associated fancj/bach1/brip1. Future Oncology, 7(2):253–261, February 2011. URL: http://dx.doi.org/10.2217/fon.10.191, doi:10.2217/fon.10.191. This article has 85 citations and is from a peer-reviewed journal.](https://doi.org/10.2217/fon.10.191)

[11. (Thanassoulas2010Thermodynamic) Angelos Thanassoulas, Michail Nomikos, Maria Theodoridou, Drakoulis Yannoukakos, Dimitris Mastellos, and George Nounesis. Thermodynamic study of the brct domain of bard1 and its interaction with the -pser-x-x-phe- motif-containing brip1 peptide. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1804(9):1908–1916, September 2010. URL: http://dx.doi.org/10.1016/j.bbapap.2010.04.012, doi:10.1016/j.bbapap.2010.04.012. This article has 11 citations.](https://doi.org/10.1016/j.bbapap.2010.04.012)

[12. (De2008A) Arcangela De Nicolo, Mariella Tancredi, Grazia Lombardi, Cristina Chantal Flemma, Serena Barbuti, Claudio Di Cristofano, Bijan Sobhian, Generoso Bevilacqua, Ronny Drapkin, and Maria Adelaide Caligo. A novel breast cancer–associated brip1 (fancj/bach1) germ-line mutation impairs protein stability and function. Clinical Cancer Research, 14(14):4672–4680, July 2008. URL: http://dx.doi.org/10.1158/1078-0432.ccr-08-0087, doi:10.1158/1078-0432.ccr-08-0087. This article has 49 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/1078-0432.ccr-08-0087)