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（由适用提供）：由MRE11，RAD50和NBS1亚基（MRN）组成的MRE11复合物对于维持基因组稳定性至关重要。 NBS1和MRE11分别与Nijmegen Breakage综合征（NBS）和催化性 - 凝集性症状样疾病（ATLD）相关，受影响的患者倾向于癌症。 MRE11复合物在DNA损伤反应和DNA双链断裂（DSB）修复中起关键作用，但尚不完全了解潜在的机制。在这项研究中，我们确定了MRE11复合物在常见的脆弱位点保护，复制叉保护和DSB修复中的新功能。我们建议进一步研究MRE11复合物在保持基因组完整性和促进哺乳动物细胞中DNA DSB修复方面作用的基础机制。首先，我们将确定MRE11复合物在保护共同脆弱位点稳定性中的作用。我们将使用新建立的Assas检查常见的脆弱位点保护，并探索MRN维持叉子稳定性和修复DSB在常见脆弱部位产生的DSB的机制。其次，我们将研究MRE11复合物的功能以保护停滞的复制叉 并通过与其他叉子稳定蛋白的特定相互作用来促进折叠叉处的修复耦合复制。第三，我们将研究MRE11复合物如何调节DSB末端的终端切除，并调节适当修复DSB的途径的利用。这些研究将揭示MRE11复合物在维持基因组稳定性方面的关键功能的基础机制，并将提供有关MRN缺乏如何导致受影响个体癌症的分子基础的见解，以及基因组稳定性的维持如何有助于人类预防人类的肿瘤发生。