Barber Louise J, Youds Jillian L, Ward Jordan D, McIlwraith Michael J, O'Neil Nigel J, Petalcorin Mark I R, Martin Julie S, Collis Spencer J, Cantor Sharon B, Auclair Melissa, Tissenbaum Heidi, West Stephen C, Rose Ann M, Boulton Simon J
DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.
Cell. 2008 Oct 17;135(2):261-71. doi: 10.1016/j.cell.2008.08.016.
Homologous recombination (HR) is an important conserved process for DNA repair and ensures maintenance of genome integrity. Inappropriate HR causes gross chromosomal rearrangements and tumorigenesis in mammals. In yeast, the Srs2 helicase eliminates inappropriate recombination events, but the functional equivalent of Srs2 in higher eukaryotes has been elusive. Here, we identify C. elegans RTEL-1 as a functional analog of Srs2 and describe its vertebrate counterpart, RTEL1, which is required for genome stability and tumor avoidance. We find that rtel-1 mutant worms and RTEL1-depleted human cells share characteristic phenotypes with yeast srs2 mutants: lethality upon deletion of the sgs1/BLM homolog, hyperrecombination, and DNA damage sensitivity. In vitro, purified human RTEL1 antagonizes HR by promoting the disassembly of D loop recombination intermediates in a reaction dependent upon ATP hydrolysis. We propose that loss of HR control after deregulation of RTEL1 may be a critical event that drives genome instability and cancer.
同源重组（HR）是DNA修复过程中一个重要的保守过程，可确保基因组完整性的维持。不适当的同源重组会导致哺乳动物出现严重的染色体重排和肿瘤发生。在酵母中，Srs2解旋酶可消除不适当的重组事件，但在高等真核生物中与Srs2功能相当的蛋白一直难以捉摸。在此，我们鉴定出秀丽隐杆线虫的RTEL-1是Srs2的功能类似物，并描述了其在脊椎动物中的对应物RTEL1，它对于基因组稳定性和肿瘤预防是必需的。我们发现rtel-1突变线虫和RTEL1缺失的人类细胞与酵母srs2突变体具有共同的特征表型：缺失sgs1/BLM同源物时出现致死性、重组增强以及对DNA损伤敏感。在体外，纯化的人类RTEL1通过在依赖ATP水解的反应中促进D环重组中间体的解离来拮抗同源重组。我们提出，RTEL1失调后同源重组控制的丧失可能是驱动基因组不稳定和癌症的关键事件。
