Genetic control of mitotic recombination in mice

小鼠有丝分裂重组的遗传控制

• 批准号: 6968854
• 负责人: GUANGBIN LUO
• 金额: $ 30.22万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-10 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968854
• 关键词: cancer risk; carcinogenesis; cell cycle; gene expression; gene targeting; genetic recombination; genetically modified animals; helicase; laboratory mouse; loss of heterozygosity; neoplastic process; tumor suppressor genes

DESCRIPTION (provided by applicant): The long-term objective of this project is to define the roles and mechanisms by which the RecQ DNA helicases regulate mitotic recombination and suppress mitotic crossover. Homologous recombination can lead to crossover, which can lead to translocations, deletions, and loss of heterozygosity (LOH), all of which have been implicated as potential cancer causing or - promoting events. Thus, in mammals, mitotic recombination is highly regulated to prevent excessive crossover. Mutations in the RecQ family member BLM give rise to Bloom syndrome; a disease typified by increased mitotic crossovers and elevated risks to cancer, underscoring the importance of RecQ helicases in the suppression of mitotic crossover and carcinogenesis. Previously, we have shown that a mouse model of Bloom syndrome has increased tumor susceptibility as a result of diminished suppression of mitotic crossover. We have now found that a second RecQ family member, mouse RecqlS, is also involved in the suppression of mitotic crossover, and that it interacts genetically with Blm in this suppression. We hypothesize that in mammals, replication demise is the primary cause of spontaneous mitotic crossover. Two independent pathways: a Blm-specific pathway and a RecqlS-specific pathway, respectively, are responsible for the restoration of stalled forks via non-recombination-based mechanism to suppress mitotic crossover and reduce cancer risk. In this application, we propose to use the knockout mouse cell lines and knockout mouse models we have created to test this hypothesis and to study the relative contributions of these two proposed pathways in the suppression of mitotic crossover and carcinogenesis. These studies will provide significant insights into the regulation of mitotic recombination and the origins of the early oncogenic LOH events during carcinogenesis.

描述（由申请人提供）：该项目的长期目标是确定 RecQ DNA 解旋酶调节有丝分裂重组和抑制有丝分裂交叉的作用和机制。 同源重组可导致交叉，从而导致易位、缺失和杂合性丧失 (LOH)，所有这些都被认为是潜在的致癌或促癌事件。因此，在哺乳动物中，有丝分裂重组受到高度调控，以防止过度交叉。 RecQ 家族成员 BLM 的突变会引发布卢姆综合征；一种以有丝分裂交叉增加和癌症风险升高为特征的疾病，强调了 RecQ 解旋酶在抑制有丝分裂交叉和癌发生中的重要性。此前，我们已经证明，布卢姆综合征的小鼠模型由于有丝分裂交叉的抑制减弱而增加了肿瘤易感性。 我们现在发现，第二个 RecQ 家族成员，小鼠 RecqlS，也参与有丝分裂交叉的抑制，并且在这种抑制中它与 Blm 存在遗传相互作用。我们假设在哺乳动物中，复制死亡是自发有丝分裂交叉的主要原因。两条独立的途径：分别是 Blm 特异性途径和 RecqlS 特异性途径，负责通过非重组机制恢复停滞的分叉，从而抑制有丝分裂交叉并降低癌症风险。在本申请中，我们建议使用我们创建的敲除小鼠细胞系和敲除小鼠模型来测试这一假设并研究这两种提议的途径在抑制有丝分裂交叉和致癌作用中的相对贡献。这些研究将为有丝分裂重组的调节和致癌过程中早期致癌 LOH 事件的起源提供重要的见解。