Roles of the RecQ Helicases BLM and RECQ5 in Genome Maintenance

描述（申请人提供）：DNA解旋酶普遍存在，数量众多，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。我们一直对一种叫做RecQ家族的独特解旋酶感兴趣，它在人类中有五个不同的成员。其中三种解旋酶（即BLM、RTS和WRN）的遗传缺陷导致与癌症易感性相关的人类综合征。重要的是，基因消融RecQ5也会在小鼠中产生癌症易感性。因此，RecQ解旋酶对于基因组的维持和癌症的避免显然是重要的。BLM解旋酶的突变是导致辐射敏感和癌症易感性疾病Bloom's综合征的原因，在同源重组（HR）介导的染色体损伤修复的两个关键阶段起作用，即DNA双链断裂的切除和双Holliday结的溶解，这是一种晚期的HR中间体。因此，BLM及其伴侣蛋白的缺陷导致同源修复启动受损、姐妹染色单体频繁交换和染色体畸变。尽管RECQ5尚未与人类疾病相关，但它在小鼠体内的消融会导致癌症易感性。缺乏recq5的细胞表现出DNA损伤敏感性，姐妹染色单体交换和HR事件升高，并且在基因毒性应激下容易发生染色体重排。RECQ5物理上与RAD51重组酶相互作用，并将RAD51从DNA中取代。这些结果暗示RECQ5作为一种肿瘤抑制因子，通过破坏RAD51-DNA核蛋白细丝来防止不适当的HR事件。在这个更新项目中，我们将努力描绘BLM在人力资源修复和

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.