Defective HDR through Homologous Recombination (HRR) due to BRCA1 loss-of-function

Stable Identifier
R-HSA-9701192
Type
Pathway
Species
Homo sapiens
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In addition to its role in DNA double-strand break (DSB) signaling, BRCA1 plays an important role in homologous recombination repair (HRR) of DSBs by directly promoting recruitment of PALB2 and indirectly BRCA2 to DSB repair sites. In addition, BRCA1 increases the speed and processivity of DNA end resection which consists of 5′–3′ nucleolytic degradation of DSBs (Cruz-Garcia et al. 2014). The direct BRCA1 interaction with PALB2 helps to fine-tune the localization of BRCA2 and RAD51 at DSBs (Zhang et al. 2009, Sy et al. 2009). PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity, thus enhancing RAD51-mediated strand exchange (branch migration) and promoting the formation of D-loop structures (synaptic complex assembly). A D-loop structure is formed when complementary duplex DNA (sister chromatid arm) is progressively invaded by the RAD51 nucleoprotein filament, with base pairing of the invading ssDNA and the complementary sister chromatid DNA strand (Sung et al. 2003).

The N-terminal region of BRCA1 contains the RING domain (residues 7-98), required for the heterodimerization of BRCA1 with BARD1. BRCA1:BARD1 heterodimer has E3 ubiquitin ligase activity which is important for DNA repair (Drost et al. 2011). Several missense mutations within the RING domain have been linked to increased risks of developing breast/ovarian cancers (Bouwman et al. 2013; Starita et al. 2018). BRCA1 mutant proteins impaired in BARD1 binding are annotated in the pathway "Defective DNA double strand break response due to BRCA1 loss of function".

The C-terminal region of BRCA1 which contains two coiled coil domains (residues 1397-1424) and two BRCT domains (residues 1642-1736 for BRCT 1; residues 1756-1855 for BRCT 2) is involved in PALB2 binding, with the second coiled coil domain being essential (Sy et al. 2009). Several cancer-associated BRCA1 missense mutants that affect the C-terminal region were shown to have reduced ability to bind PALB2 (Sy et al. 2009). In addition, many nonsense and frameshift mutations in BRCA1 reported in cancer result in truncated proteins that lack the PALB2-binding domain.

Literature References
PubMed ID Title Journal Year
20871616 Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2

Dray, E, Etchin, J, Wiese, C, Saro, D, Williams, GJ, Hammel, M, Yu, X, Galkin, VE, Liu, D, Tsai, MS, Sy, SM, Schild, D, Egelman, E, Chen, J, Sung, P

Nat. Struct. Mol. Biol. 2010
30219179 A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function

Starita, LM, Islam, MM, Banerjee, T, Adamovich, AI, Gullingsrud, J, Fields, S, Shendure, J, Parvin, JD

Am J Hum Genet 2018
23867111 A high-throughput functional complementation assay for classification of BRCA1 missense variants

Bouwman, P, van der Gulden, H, van der Heijden, I, Drost, R, Klijn, CN, Prasetyanti, P, Pieterse, M, Wientjens, E, Seibler, J, Hogervorst, FB, Jonkers, J

Cancer Discov 2013
19268590 PALB2 links BRCA1 and BRCA2 in the DNA-damage response

Zhang, F, Ma, J, Wu, J, Ye, L, Cai, H, Xia, B, Yu, X

Curr. Biol. 2009
19369211 PALB2 is an integral component of the BRCA complex required for homologous recombination repair

Sy, SM, Huen, MS, Chen, J

Proc Natl Acad Sci U S A 2009
17996711 Promotion of homologous recombination and genomic stability by RAD51AP1 via RAD51 recombinase enhancement

Wiese, C, Dray, E, Groesser, T, San Filippo, J, Shi, I, Collins, DW, Tsai, MS, Williams, GJ, Rydberg, B, Sung, P, Schild, D

Mol. Cell 2007
12912992 Rad51 recombinase and recombination mediators.

Sung, P, Krejci, L, Van Komen, S, Sehorn, MG

J Biol Chem 2003
20871615 Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination

Buisson, R, Dion-Côté, AM, Coulombe, Y, Launay, H, Cai, H, Stasiak, AZ, Stasiak, A, Xia, B, Masson, JY

Nat. Struct. Mol. Biol. 2010
22172724 BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance

Drost, R, Bouwman, P, Rottenberg, S, Boon, U, Schut, E, Klarenbeek, S, Klijn, C, van der Heijden, I, van der Gulden, H, Wientjens, E, Pieterse, M, Catteau, A, Green, P, Solomon, E, Morris, JR, Jonkers, J

Cancer Cell 2011
25310973 BRCA1 accelerates CtIP-mediated DNA-end resection

Cruz-García, A, López-Saavedra, A, Huertas, P

Cell Rep 2014
17996710 RAD51AP1 is a structure-specific DNA binding protein that stimulates joint molecule formation during RAD51-mediated homologous recombination

Modesti, M, Budzowska, M, Baldeyron, C, Demmers, JA, Ghirlando, R, Kanaar, R

Mol. Cell 2007
Participants
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Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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