Roles of the RecQ Helicases BLM and RECQ5 in Genome Maintenance

描述（由申请人提供）：DNA解旋酶普遍存在且数量巨大，在染色体代谢的各个方面发挥重要作用，包括转录、DNA复制和DNA修复。我们一直对一类独特的解旋酶感兴趣，称为RecQ家族，在人类中有五个不同的成员。这些解旋酶中的三种存在遗传缺陷，即，BLM、RTS和WRN引起与癌症易感性相关的人类综合征。重要的是，RecQ 5的基因切除也会导致小鼠的癌症易感性。因此，RecQ解旋酶对于基因组维持和癌症避免显然是重要的。BLM解旋酶是辐射敏感性和癌症易感性疾病Bloom综合征的原因，其在同源重组（HR）介导的染色体损伤修复的两个关键阶段发挥作用，即在DNA双链断裂的切除和双Holliday连接（晚期HR中间体）的溶解中。因此，BLM及其伴侣蛋白的缺陷会导致同源修复启动受损、频繁的姐妹染色单体交换和染色体畸变。尽管RECQ 5尚未与人类疾病相关，但其在小鼠中的消融导致癌症易感性。RECQ 5缺陷细胞表现出DNA损伤敏感性、姐妹染色单体交换和HR事件升高，并且在遗传毒性应激时易于发生染色体重排。RECQ 5与RAD 51重组酶物理相互作用并从DNA中置换RAD 51。这些结果表明RECQ 5是一种肿瘤抑制因子，通过破坏RAD 51-DNA核蛋白丝来防止不适当的HR事件。在这个更新项目中，我们将努力描绘BLM在人力资源修复中的多方面作用， 调节，并定义RECQ 5作为抗重组酶的新作用的机制。

DESCRIPTION (provided by applicant): DNA helicases are ubiquitous and vast in number, serving important roles in various facets of chromosome metabolism, including transcription, DNA replication, and DNA repair. We have been interested in a unique class of helicases called the RecQ family, with five distinct members in humans. Genetic defects in three of these helicases, viz., BLM, RTS, and WRN, give rise to human syndromes associated with cancer predisposition. Importantly, genetic ablation of RecQ5 also engenders cancer susceptibility in mice. Thus, the RecQ helicases are clearly important for genome maintenance and cancer avoidance. The BLM helicase, mutations in which being the cause of the radiation-sensitive and cancer-prone disorder Bloom's syndrome, functions in two critical stages of homologous recombination (HR)- mediated chromosome damage repair, namely, in the resection of DNA double-strand breaks and the dissolution of the double Holliday Junction, a late HR intermediate. Defects in BLM and its partner proteins thus lead to impaired initiation of homologous repair, frequent sister chromatid exchanges, and chromosome aberrations. Even though RECQ5 has not yet been associated with a human disease, its ablation in mice results in cancer susceptibility. RECQ5-deficient cells exhibit DNA damage sensitivity, elevated sister chromatid exchanges and HR events, and are prone to chromosomal rearrangements upon genotoxic stress. RECQ5 physically interacts with the RAD51 recombinase and displaces RAD51 from DNA. These results implicate RECQ5 as a tumor suppressor that acts by preventing inappropriate HR events via the disruption of RAD51-DNA nucleoprotein filaments. In this renewal project, we will strive to delineate the multi-faceted role of BLM in HR repair and regulation, and to also define the mechanism underlying the novel role of RECQ5 as an anti-recombinase.