RecqL4, chromosome instability and cancer predisposition

RecqL4、染色体不稳定性和癌症易感性

• 批准号: 7361389
• 负责人: GUANGBIN LUO
• 金额: $ 26.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-08 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7361389
• 关键词: Affect; Age; Aging; Aneuploidy; Binding; Cancerous; Cell Aging; Cell Cycle; Cell Cycle Stage; Cell Death; Cells; Centromere; Chimeric Proteins; Chromatin; Chromosomal Instability; Chromosome Segregation; Class; DNA Damage; Data; Defect; Embryo; Ensure; Environment; Eukaryota; Eukaryotic Cell; Family; Fibroblasts; Frequencies; Goals; Hand; Harvest; Hereditary Disease; Homologous Gene; Human; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Life; Link; Malignant Neoplasms; Mitosis; Mitotic/Spindle Checkpoint; Molecular; Mus; Mutant Strains Mice; Mutation; Phenotype; Play; Predisposition; Premature aging syndrome; Prometaphase; RECQL4 gene; Role; Severities; Sister Chromatid; Solid Neoplasm; Syndrome; Testing; Therapeutic Intervention; Transgenic Organisms; Upper arm; Western Blotting; Work; base; cancer therapy; carcinogenesis; cellular imaging; cohesin; cohesion; embryonic stem cell; helicase; irradiation; mouse model; novel; research study; tool; tumor initiation; tumor progression

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.

该提案的长期目标是了解其分子机制 Recql4 影响有丝分裂过程中的染色体分离以及 Recql4 缺陷在有丝分裂过程中的作用 小鼠的致癌和过早衰老。 非整倍性是人类实体瘤的标志。虽然仍不确定是否 染色体不稳定性在肿瘤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 那些由治疗干预引起的。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， 造成染色体不稳定的机制尚未完全了解。我们有 创建了 II 型 Rothmund-f homson 综合征 (RTS) 的 Recql4 基因敲除小鼠模型， 由 RECQL4 突变引起的易患癌症的遗传性疾病。 RECQL4 编码其中之一 人类 DNA 解旋酶 RecQ 家族的五个同源物。 Recql4基因敲除小鼠 概括了 II 型 RTS 的所有主要表型，包括染色体不稳定、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 发现着丝粒过早分离是非整倍体、癌症的根本原因 这些小鼠的易感性，或许还有过早衰老。因此，这些基因敲除小鼠 为研究染色体不稳定的新机制和独特的机制提供了强大的工具 癌症与衰老之间的联系机制。在这里我们建议进一步定义分子 Recql4 参与姐妹染色单体凝聚和染色体的机制 隔离；以及 Recql4 敲除小鼠中癌症与衰老的联系机制。这些 研究将增进我们对染色体控制机制的理解 不稳定性以及这些机制如何导致致癌和衰老。此外，它 还可能产生治疗癌症的新靶点或策略。