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有丝分裂过程中Recql4影响染色体分离的分子机制，以及Recql4缺乏在小鼠癌变和早衰中的作用。非整倍体是人类实体肿瘤的标志。虽然染色体不稳定性是否在肿瘤发生中起促进作用仍不确定，但很明显，它为癌细胞提供了对不断变化的微环境的巨大适应性，包括那些由治疗干预带来的微环境。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，导致染色体不稳定的机制尚未完全了解。我们已经建立了II型rothmond - thomson综合征（RTS）的Recql4敲除小鼠模型，RTS是一种由Recql4突变引起的易患癌症的遗传疾病。RECQL4编码人类DNA解旋酶RecQ家族的五个同源物之一。Recql4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、癌症易感性和早衰。我们对这种敲除小鼠模型的研究发现，着丝粒过早分离是这些小鼠非整倍体、癌症易感性和可能过早衰老的潜在原因。因此，这些基因敲除小鼠为研究染色体不稳定性的新机制和癌症与衰老之间的独特机制提供了强有力的工具。本文拟进一步明确Recql4参与姐妹染色单体内聚和染色体分离的分子机制；以及在Recql4基因敲除小鼠中癌症和衰老之间的联系机制。这些研究将促进我们对控制染色体不稳定性的机制以及这些机制如何促进致癌和衰老的理解。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.