RecqL4, chromosome instability and cancer predisposition

这一提议的长期目标是了解 在有丝分裂过程中，Recql4对染色体分离的影响以及Recql4缺乏在其中的作用 小鼠的致癌和早衰。 非整倍体是人类实体瘤的一个特征。虽然目前还不确定是否 染色体不稳定性在肿瘤的发生中起着重要作用，很明显，它提供了 癌细胞对其不断变化的微环境具有很强的适应性，包括 那些由治疗干预带来的疾病。另一方面，染色体 不稳定可能是癌症和衰老之间的一个重要联系。然而， 染色体不稳定的机制还没有完全弄清楚。我们有 建立了II型Rothmund-f Homson综合征(RTS)的Recql4基因敲除小鼠模型，a 由RECQL4基因突变引起的易患癌症的遗传疾病。RECQL4编码其中一个 人类DNA解旋酶RecQ家族的五个同源物。Recq14基因敲除小鼠 概述II型RTS的所有主要表型，包括染色体不稳定、癌症 易感性和过早衰老。我们对这种基因敲除小鼠模型的研究导致了 发现着丝粒过早分离是导致非整倍体、癌症的根本原因 易感性，也许是这些小鼠的过早衰老。因此，这些基因敲除的小鼠 为研究染色体不稳定的新机制提供了强有力的工具和独特的 将癌症和衰老联系起来的机制。在这里，我们建议进一步定义分子 RecqL4参与姐妹染色单体聚集和染色体的机制 分离；以及在Recq14基因敲除小鼠中癌症和衰老的联系机制。这些 研究将促进我们对支配染色体的机制的理解 不稳定以及这些机制如何导致癌症发生和衰老。此外，它还 也可能导致癌症治疗的新靶点或策略。

The long terrh goals of this proposal are to understand the molecular mechanism by which Recql4 affects chromosome segregation during mitosis and the role of Recql4 deficiency in carcinogenesis and premature aging in mice. Aneuploidy is a hallmark of human solid tumors. While it remains uncertain whether chromosome instability plays a contributing role in tumor initiation, it is clear that it provides cancerous cells with the great adaptability to their ever changing microenvironments, including those that are brought about by therapeutic interventions. On the other hand, chromosomal instability may represent an important link between cancer and3 aging. However, the mechanisms responsible for chromosomal instability have not been fully understood. We have created a Recql4 knockout mouse model for Type II Rothmund-f homson syndrome (RTS), a cancer-prone genetic disorder caused by mutations in RECQL4. RECQL4 encodes one of the five homologues of the RecQ family of DNA helicases in humans. Recql4 knockout mice recapitulate all the major phenotypes of Type II RTS, including chromosome instability, cancer predisposition and premature aging. Our studies on this knockout mouse model have led to the discovery that premature centromere separation is the underlying cause of aneuploidy, cancer predisposition, and perhaps premature aging in these mice. Thus, these knockout mice provide a powerful tool to study a novel mechanism of chromosomal instability and a unique mechanism that links cancer and aging. Here we propose to further define the molecular mechanism by which Recql4 is involved in sister-chromatid cohesion and chromosome segregation; and the mechanism that links cancer and aging in Recql4 knockout mice. These studies will advance our understanding regarding the mechanisms that govern chromosome instability and how these mechanisms contribute to carcinogenesis and aging. Furthermore, it may also result in novel targets or strategies for treatments of cancer.