DNA Damage & DNA Replication: a Complex Relationship

DNA损伤

• 批准号: 10221003
• 负责人: John HJ Petrini
• 金额: $ 94.96万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10221003
• 关键词: ATM activation; ATM function; Address; Affect; Animal Model; Area; Biochemistry; Chromosomal Instability; Complex; DNA; DNA Damage; DNA Repair; DNA Replication Damage; DNA biosynthesis; DNA replication fork; Defect; Development; Eukaryota; Genetic Screening; Genome Stability; Genomic Instability; Goals; Health; Human; Human Chromosomes; Immune; Laboratories; Light; Maintenance; Malignant Neoplasms; Mining; Modeling; Mus; Mutation; Neurologic; Pancytopenia; Process; Proteins; Recurrent tumor; Resources; Risk; Role; Signal Transduction; Syndrome; Untranslated RNA; Work; Yeasts; ataxia telangiectasia mutated protein; cancer genomics; experimental study; genomic data; helicase; human disease; insight; mouse genetics; repair function; replication stress; reproductive; response; structural biology; telomere; yeast genetics

PROJECT SUMMARY/ABSTRACT Our overarching goals are: i. to define the mechanism(s) of ATM activation by the Mre11 complex; ii. to define the role(s) of the Mre11 complex in DNA replication; iii. To define the role(s) of the Mre11 complex in response to DNA replication stress. As part of the emphasis of DNA replication stress, our focus includes RTEL1 which acts to mitigate replication stress at the telomere. A combination of yeast and mouse genetics, biochemistry, and structural biology are employed to address these issues. Our previous work on these topics led to substantial scientific progress and insight regarding processes relevant to human health. Specific areas of inquiry are: • Genetic screens in yeast and mining of cancer genomic data revealed separation of function Rad50 mutations that affect ATM dependent DNA damage signaling without affecting the DNA repair functions of the Mre11 complex. These mutations constitute a resource for deciphering the mechanism by which the Mre11 complex activates the ATM kinase to initiate DNA damage signaling. • We have modeled three recurrent tumor borne mutations in mice that were confirmed to be hypomorphic for ATM activation but proficient in DNA repair. These animal models offer a unique opportunity to delineate Mre11 complex-dependent ATM functions. • We have identified factors that function at the DNA replication fork in a manner that depends on the Mre11 complex. An important focus of our laboratory is to understand the functional role(s) of those factors. Defects in factors that promote accurate DNA replication are highly correlated with human disease, and so understanding this fundamental process is an important priority in our work. • Whereas the Mre11 complex functions at the replication fork, RTEL1 is a helicase that promotes accurate replication of telomeric DNA. We have discovered that RTEL1 influences the abundance and disposition of a long non coding RNA, called TERRA, that is transcribed from the subtelomeric regions of all eukaryotes. Our goal in this aspect of our work is two fold. First, to understand the role of RTEL1 in maintaining telomere stability. Second, to use that information to shed light on the function of TERRA, which is a long standing question.

项目摘要/摘要 我们的总体目标是：i。通过MRE11复合物来定义ATM激活的机制； ii。到 定义MRE11复合物在DNA复制中的作用； iii。定义MRE11复合物中的作用 对DNA复制应力的响应。作为DNA复制压​​力重点的一部分，我们的重点包括 RTEL1可用于减轻端粒的复制应力。酵母和小鼠遗传学的结合， 生物化学和结构生物学用于解决这些问题。我们以前关于这些主题的工作 导致了与人类健康相关的过程的实质科学进步和洞察力。特定区域 查询是： •酵母中的遗传筛选和癌症基因组数据的挖掘显示功能RAD50的分离 影响ATM依赖的DNA损伤信号传导的突变，而不会影响DNA修复功能 MRE11复合物的。这些突变构成了破译机制的资源 MRE11复合物激活ATM激酶以启动DNA损伤信号传导。 •我们已经对小鼠中的三个复发性肿瘤传播突变进行了建模，这些突变被证实为 超然的ATM激活，但精通DNA修复。这些动物模型提供了独特的 划定MRE11复合依赖性ATM功能的机会。 •我们已经确定了在DNA复制叉处发挥作用的因素，其方式取决于 MRE11复合物。我们实验室的一个重要重点是了解那些的功能作用 因素。促进准确DNA复制因素的缺陷与人高度相关 疾病，因此了解这一基本过程是我们工作的重要重点。 •虽然MRE11复合物在复制叉处的功能，但RTEL1是一种促进的解旋酶 准确复制远程DNA。我们发现RTEL1影响了抽象和 从子telomeric区域转录的长的非编码RNA（称为Terra）的性格 在所有真核生物中。我们在工作的这一方面的目标是两倍。首先，了解RTEL1的作用 保持端粒稳定性。其次，要使用这些信息来阐明 Terra，这是一个长期的问题。