Replication blocking lesions present a unique substrate for homologous recombination

被引:64
作者
Ward, Jordan D.
Barber, Louise J.
Petalcorin, Mark I. R.
Yanowitz, Judith
Boulton, Simon J.
机构
[1] Imperial Canc Res Fund, Clare Hall Labs, DNA Damage Response Lab, Canc Res UK,London Res Inst, S Mimms EN6 3LD, Herts, England
[2] Carnegie Inst, Dept Embryol, Baltimore, MD USA
关键词
C; elegans; homologous recombination; ICL repair; Rad51; paralogs; replication fork barriers;
D O I
10.1038/sj.emboj.7601766
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Homologous recombination (HR) plays a critical role in the restart of blocked replication forks, but how this is achieved remains poorly understood. We show that mutants in the single Rad51 paralog in Caenorhabditis elegans, rfs-1, permit discrimination between HR substrates generated at DNA double-strand breaks (DSBs), or following replication fork collapse from HR substrates assembled at replication fork barriers (RFBs). Unexpectedly, RFS-1 is dispensable for RAD-51 recruitment to meiotic and ionizing radiation (IR)-induced DSBs and following replication fork collapse, yet, is essential for RAD-51 recruitment to RFBs formed by DNA cross-linking agents and other replication blocking lesions. Deletion of rfs-1 also suppresses the accumulation of toxic HR intermediates in him-6; top-3 mutants and accelerates deletion formation at presumed endogenous RFBs formed by poly G/C tracts in the absence of DOG-1. These data suggest that RFS-1 is not a general mediator of HR-dependent DSB repair, but acts specifically to promote HR at RFBs. HR substrates generated at conventional DSBs or following replication fork collapse are therefore intrinsically different from those produced during normal repair of blocked replication forks.
引用
收藏
页码:3384 / 3396
页数:13
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