Role of the Mre11 complex in the maintenance of genome stability

Mre11复合物在维持基因组稳定性中的作用

• 批准号: 9107833
• 负责人: Xiaohua Wu
• 金额: $ 44.03万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-08 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107833
• 关键词: Address; Affect; Applications Grants; Biological; Biological Assay; Biological Process; Chromosomal Rearrangement; Chromosome Fragile Sites; Complex; Coupled; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence; DNA biosynthesis; DNA replication fork; Development; Double Strand Break Repair; Equilibrium; Event; Excision; Functional disorder; Genes; Genome Stability; Genomic Instability; Genomic Segment; Health; Human; Individual; Lead; Link; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Mitotic Recombination; Molecular; Mutation; Nijmegen Breakage Syndrome; Nonhomologous DNA End Joining; Oncogenes; Pathway interactions; Patients; Phosphorylation; Play; Premalignant; Prevention; Proteins; Recruitment Activity; Regulation; Role; S Phase; Site; Staging; Stress; Stretching; Therapeutic Intervention; Work; ataxia-telangiectasia like disorder; base; cancer cell; cancer prevention; genome integrity; homologous recombination; human disease; insight; novel; prevent; repaired; response; tumorigenesis

 DESCRIPTION (provided by applicant): The Mre11 complex, composed of Mre11, Rad50 and Nbs1 subunits (MRN), is essential for the maintenance of genome stability. Nbs1 and Mre11 are linked to the Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively, and the affected patients are predisposed to cancer. The Mre11 complex plays a critical role in DNA damage response and DNA double-strand break (DSB) repair, but the underlying mechanisms are not fully understood. In this study, we identified new functions of the Mre11 complex in common fragile site protection, replication fork protection and DSB repair. We propose to further investigate the mechanisms underlying the role of the Mre11 complex in preserving genome integrity and promoting DNA DSB repair in mammalian cells. First, we will determine the role of the Mre11 complex in the protection of common fragile site stability. We will use newly established assays to examine common fragile site protection and explore the mechanisms of MRN to maintain fork stability and repair DSBs generated at common fragile sites. Second, we will study the function of the Mre11 complex to protect stalled replication forks and to promote repair-coupled replication restart at collapsed forks through specific interactions with other fork stabilizing proteins. Third, we will investigate how the Mre11 complex modulates end resection at DSB ends and regulates the utilization of appropriate pathways to repair DSBs. These studies will reveal the molecular mechanisms underlying the critical functions of the Mre11 complex in the maintenance of genome stability and will provide insights into the molecular basis of how MRN deficiency leads to cancer in affected individuals and how maintenance of genome stability contributes to the prevention of tumorigenesis in humans.

 描述（由申请人提供）：Mre11 复合物由 Mre11、Rad50 和 Nbs1 亚基 (MRN) 组成，对于维持基因组稳定性至关重要，Nbs1 和 Mre11 与奈梅亨断裂综合征 (NBS) 和共济失调毛细血管扩张症有关。 Mre11 复合物在 DNA 损伤中发挥着关键作用。反应和DNA双链断裂（DSB）修复，但其潜在机制尚未完全了解。在本研究中，我们发现了Mre11复合物在常见脆弱位点保护、复制叉保护和DSB修复方面的新功能，我们建议进一步研究。研究 Mre11 复合物在哺乳动物细胞中保持基因组完整性和促进 DNA DSB 修复的作用机制 首先，我们将确定 Mre11 复合物在保护常见脆弱位点稳定性中的作用。检查常见的脆弱性其次，我们将研究 Mre11 复合物保护停滞复制叉的功能。 第三，我们将研究 Mre11 复合物如何调节 DSB 末端的末端切除并调节修复 DSB 的适当途径的利用。 Mre11 复合物在维持基因组稳定性方面的关键功能背后的分子机制，并将提供对 MRN 缺陷如何导致受影响个体癌症的分子基础以及维持基因组稳定性如何有助于预防癌症的分子基础的见解。人类肿瘤发生。