Bernstein Kara A, Shor Erika, Sunjevaric Ivana, Fumasoni Marco, Burgess Rebecca C, Foiani Marco, Branzei Dana, Rothstein Rodney
Department of Genetics & Development, Columbia University Medical Center, New York, NY 10032, USA.
EMBO J. 2009 Apr 8;28(7):915-25. doi: 10.1038/emboj.2009.28. Epub 2009 Feb 12.
Mutations in human homologues of the bacterial RecQ helicase cause diseases leading to cancer predisposition and/or shortened lifespan (Werner, Bloom, and Rothmund-Thomson syndromes). The budding yeast Saccharomyces cerevisiae has one RecQ helicase, Sgs1, which functions with Top3 and Rmi1 in DNA repair. Here, we report separation-of-function alleles of SGS1 that suppress the slow growth of top3Delta and rmi1Delta cells similar to an SGS1 deletion, but are resistant to DNA damage similar to wild-type SGS1. In one allele, the second acidic region is deleted, and in the other, only a single aspartic acid residue 664 is deleted. sgs1-D664Delta, unlike sgs1Delta, neither disrupts DNA recombination nor has synthetic growth defects when combined with DNA repair mutants. However, during S phase, it accumulates replication-associated X-shaped structures at damaged replication forks. Furthermore, fluorescent microscopy reveals that the sgs1-D664Delta allele exhibits increased spontaneous RPA foci, suggesting that the persistent X-structures may contain single-stranded DNA. Taken together, these results suggest that the Sgs1 function in repair of DNA replication intermediates can be uncoupled from its role in homologous recombinational repair.
细菌RecQ解旋酶的人类同源物发生突变会导致疾病,引发癌症易感性和/或缩短寿命(沃纳综合征、布卢姆综合征和罗思蒙德-汤姆森综合征)。芽殖酵母酿酒酵母有一个RecQ解旋酶Sgs1,它在DNA修复中与Top3和Rmi1共同发挥作用。在此,我们报告了SGS1的功能分离等位基因,这些等位基因抑制top3Δ和rmi1Δ细胞的缓慢生长,类似于SGS1缺失,但对DNA损伤具有抗性,类似于野生型SGS1。在一个等位基因中,第二个酸性区域被删除,在另一个等位基因中,仅单个天冬氨酸残基664被删除。与sgs1Δ不同,sgs1-D664Δ既不破坏DNA重组,与DNA修复突变体结合时也没有合成生长缺陷。然而,在S期,它在受损的复制叉处积累与复制相关的X形结构。此外,荧光显微镜检查显示,sgs1-D664Δ等位基因表现出自发RPA病灶增加,这表明持续的X结构可能含有单链DNA。综上所述,这些结果表明,Sgs1在DNA复制中间体修复中的功能可以与其在同源重组修复中的作用分离。