BRCA2/RAD51 pathway in the response to stalled forks

A model for the BRCA2/RAD51 pathway in the response to stalled forks. After their recruitment by BRCA1/MRN, BRCA2/RAD51 complexes may act in concert to (i) disassemble chromatin (A); (ii) maintain SCC/alignment (B); (iii) effectuate strand-switching and thereby recruit/activate ATR to enhance SCC/alignment (C); (iv) provide one DSB end, and thereby activate ATM and DNA-PK (D); and (v) twist the DSB end after its processing at least by error-free TLS polymerases into leading and lagging strands that would anneal back with the original templates, and thereby yield a hemicatenane (E). If needed, the harmless DSB end (D and F) may engage in HR, NHEJ or SSA between neighbouring stalled forks during termination of the replication (S) phase (not shown). By interfering with ATR recruitment/activation, short EMSY could induce RFR (RAD51-independent HR) and chicken-foot formation (F). HJ-resolving enzymes against crossover, such as BLM and WRN, may prevent fork collapse (G) by competing with HJ-nicking enzymes (red arrows) at the expense of CIN. Unlike hyper-recombination, BRCA2/RAD51-mediated strand switching at either stalled forks (hemicatenation/RFR) or DSBs does not require RAD51-filament formation, in which case the fourfold decrease in HR repair of I-SceI-induced DSBs by short EMSY could be attributed to apoptosis/senescence rather than decreased efficiency of strand switching. Consistently, meiotic HR does not require the loading of RAD51 oligomers by BRCA2 at programmed DSBs, since BRCA2∆ex27 KO mice are as fertile as wild-type animals, except that they exhibit hypersensitivity to IR, senescence and reduced life span. Thus, whereas BRCA2/RAD51-mediated strand switching ensures survival, maintains chromosomal stability and acts as an anti-cancer barrier, SCRS and RAD51-mediated strand exchange/invasion can compete with RFR for ssDNA and thereby decrease the likelihood of forks collapse at the expense of CIN and human diseases. Only abnormally proliferating cells crippled in an essential gene are prone to gene mutation/reversion and fork collapse

Publication

EMSY overexpression disrupts the BRCA2/RAD51 pathway in the DNA-damage response: implications for chromosomal instability/recombination syndromes as checkpoint diseases. (2011) Isabelle Cousineau, et al. Mol Genet Genomics. 2011 Apr;285(4):325-340. Figure: F5. All organisms Homo sapiens Drosophila melanogaster Danio rerio

Disease mentions