RecqL4, chromosome instability and cancer predisposition

RecqL4、染色体不稳定性和癌症易感性

• 批准号: 7761300
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761300
• 关键词: Affect; Aging; Aneuploidy; Binding; Cancerous; Cell Aging; Cell Cycle; Cell Cycle Stage; Cell Death; Cells; Centromere; Chimeric Proteins; Chromatin; Chromosomal Instability; Chromosome Segregation; DNA Damage; Data; Defect; Embryo; Ensure; Environment; Eukaryota; Family; Fibroblasts; Frequencies; Goals; Hand; Harvest; Hereditary Disease; Homologous Gene; Human; 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 Mice; Western Blotting; Work; arm; base; cancer therapy; carcinogenesis; cellular imaging; cohesin; cohesion; embryonic stem cell; helicase; irradiation; mouse model; novel; premature; research study; tool; treatment strategy; 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.

这项提议的长期目标是了解分子机制， Recql 4影响有丝分裂过程中的染色体分离以及Recql 4缺陷在有丝分裂中的作用 致癌和过早衰老。 非整倍体是人类实体瘤的标志。虽然目前还不确定， 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 癌细胞对不断变化的微环境具有很强的适应性， 这些都是由治疗干预引起的。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。但 导致染色体不稳定性的机制尚未完全了解。我们有 建立了II型Rothmund-f homson综合征（RTS）的Recql 4敲除小鼠模型， 由RECQL 4突变引起的易患癌症的遗传疾病。RECQL 4编码其中一个 人类DNA解旋酶RecQ家族的五种同系物。Recql 4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已经导致了 发现过早的着丝粒分离是非整倍体，癌症， 易感性，也许是这些小鼠的过早衰老。因此，这些基因敲除小鼠 为研究染色体不稳定性的新机制提供了强有力的工具， 癌症和衰老之间的联系在这里，我们建议进一步定义分子 Recql 4参与姐妹染色单体凝聚和染色体 分离;以及在Recql 4敲除小鼠中将癌症和衰老联系起来的机制。这些 这些研究将促进我们对控制染色体的机制的理解 不稳定性以及这些机制如何导致致癌和衰老。而且 也可能导致癌症治疗的新靶点或策略。