RecqL4, chromosome instability and cancer predisposition

描述（由申请人提供）：本提案的长期目标是了解Recql 4在有丝分裂期间影响染色体分离的分子机制以及Recql 4缺陷在小鼠致癌和早衰中的作用。非整倍体是人类实体瘤的标志。虽然尚不确定染色体不稳定性是否在肿瘤发生中起作用，但很明显，它为癌细胞提供了对其不断变化的微环境的巨大适应性，包括治疗干预所带来的微环境。另一方面，染色体不稳定性可能是癌症和衰老之间的重要联系。然而，染色体不稳定性的机制尚未完全了解。我们已经创建了Recql 4敲除小鼠模型，用于II型Rothmund-Thomson综合征（RTS），这是一种由RECQL 4突变引起的易患癌症的遗传性疾病。RECQL 4编码人类DNA解旋酶RecQ家族的五个同源物之一。Recql 4敲除小鼠概括了II型RTS的所有主要表型，包括染色体不稳定性、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发现，过早的着丝粒分离是这些小鼠非整倍性、癌症易感性和可能的过早衰老的根本原因。因此，这些基因敲除小鼠为研究染色体不稳定性的新机制以及将癌症和衰老联系起来的独特机制提供了有力的工具。在这里，我们建议进一步定义Recql 4参与姐妹染色单体凝聚和染色体分离的分子机制;以及Recql 4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染色体不稳定性机制的理解，以及这些机制如何促进致癌和衰老。此外，它还可能导致癌症治疗的新靶点或策略。

DESCRIPTION (provided by applicant): The long term 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 and 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-Thomson 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.