Rad51 Paralogs Remodel Pre-synaptic Rad51 Filaments to Stimulate Homologous Recombination

• Autoři: TAYLOR Martin R. G.; ŠPÍREK Mário; CHAURASIYA Kathy R.; WARD Jordan D.; CARZANIGA Raffaella; YU Xiong; EGELMAN Edward H.; COLLINSON Lucy M.; RUEDA David; KREJČÍ Lumír; BOULTON Simon J.
• Rok publikování: 2015
• Druh: Článek v odborném periodiku
• Časopis / Zdroj: Cell
• Fakulta / Pracoviště MU: Lékařská fakulta
• Doi: http://dx.doi.org/10.1016/j.cell.2015.06.015
• Obor: Genetika a molekulární biologie
• Klíčová slova: STRAND BREAK REPAIR; CANCER SUSCEPTIBILITY GENE; RECA PROTEIN; FANCONI-ANEMIA; DNA-DAMAGE; SACCHAROMYCES-CEREVISIAE; GERMLINE MUTATIONS; OVARIAN-CANCER; BRCA2; PROMOTES
• Popis: Repair of DNA double strand breaks by homologous recombination (HR) is initiated by Rad51 filament nucleation on single-stranded DNA (ssDNA), which catalyzes strand exchange with homologous duplex DNA. BRCA2 and the Rad51 paralogs are tumor suppressors and critical mediators of Rad51. To gain insight into Rad51 paralog function, we investigated a heterodimeric Rad51 paralog complex, RFS-1/RIP-1, and uncovered the molecular basis by which Rad51 paralogs promote HR. Unlike BRCA2, which nucleates RAD-51-ssDNA filaments, RFS-1/RIP-1 binds and remodels pre-synaptic filaments to a stabilized, "open,'' and flexible conformation, in which the ssDNA is more accessible to nuclease digestion and RAD-51 dissociation rate is reduced. Walker box mutations in RFS-1, which abolish filament remodeling, fail to stimulate RAD-51 strand exchange activity, demonstrating that remodeling is essential for RFS-1/RIP-1 function. We propose that Rad51 paralogs stimulate HR by remodeling the Rad51 filament, priming it for strand exchange with the template duplex.

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