DNA Damage & DNA Replication: a Complex Relationship

DNA损伤

• 批准号: 10799031
• 负责人: John HJ Petrini
• 金额: $ 9.34万
• 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/10799031
• 关键词: ATM activation; ATM function; Address; Affect; Animal Model; Area; Award; Biochemistry; Bone marrow failure; Chromosomal Instability; Complex; DNA; DNA Damage; DNA Repair; DNA biosynthesis; DNA replication fork; Defect; Development; Eukaryota; Genetic Screening; Genetic Transcription; Genome Stability; Genomic Instability; Goals; Health; Human; Human Chromosomes; Immune; Laboratories; Maintenance; Malignant Neoplasms; Mining; Modeling; Mus; Mutation; Neurologic; Parents; 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

“This is from the Parent Award. No changes.” 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.

“这是家长奖。没有变化。” 我们的首要目标是：i.定义ATM激活的机制， Mre 11复合物; ii.定义Mre 11复合物在DNA复制中的作用; iii.到 定义Mre 11复合物在响应DNA复制应激中的作用。一部分 在DNA复制应激的重点中，我们的重点包括RTEL 1，它的作用是 减轻端粒的复制压力。酵母和老鼠基因的结合， 生物化学和结构生物学被用来解决这些问题。我们 以前关于这些主题的工作导致了实质性的科学进展和对以下方面的见解： 与人类健康相关的过程。调查的具体领域是： ·酵母中的遗传筛选和癌症基因组数据的挖掘揭示了分离 影响ATM依赖性DNA损伤信号传导的功能Rad 50突变 而不影响Mre 11复合物的DNA修复功能。这些 突变构成了一个资源，用于破译的机制， Mre 11复合物激活ATM激酶以启动DNA损伤信号传导。 ·我们在小鼠中模拟了三种复发性肿瘤携带突变， 被证实是ATM激活的亚晶型，但精通DNA修复。 这些动物模型提供了一个独特的机会，描绘Mre 11复合体- ATM功能。 ·我们已经确定了在DNA复制叉中起作用的因素， 这取决于Mre 11复合体。我们实验室的一个重点是 了解这些因素的功能作用。促进因素的缺陷 准确的DNA复制与人类疾病高度相关， 理解这一基本进程是我们工作中的一个重要优先事项。 ·尽管Mre 11复合体在复制叉处起作用，但RTEL 1是一个复制叉。 促进端粒DNA精确复制解旋酶。我们有 发现RTEL 1影响了一个长非 编码RNA，称为TERRA，它是从端粒下区域转录的， 所有的真核生物。我们在这方面的工作有两个目标。一是 了解RTEL 1在维持端粒稳定性中的作用。第二，使用 这些信息揭示了TERRA的功能，这是一个长期存在的 问题

项目成果

RTEL1 influences the abundance and localization of TERRA RNA.

• DOI: 10.1038/s41467-021-23299-2
• 发表时间: 2021-05-21
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Ghisays F;Garzia A;Wang H;Canasto-Chibuque C;Hohl M;Savage SA;Tuschl T;Petrini JHJ
• 通讯作者: Petrini JHJ

A Disease-Causing Single Amino Acid Deletion in the Coiled-Coil Domain of RAD50 Impairs MRE11 Complex Functions in Yeast and Humans.

• DOI: 10.1016/j.celrep.2020.108559
• 发表时间: 2020-12-29
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Chansel-Da Cruz M;Hohl M;Ceppi I;Kermasson L;Maggiorella L;Modesti M;de Villartay JP;Ileri T;Cejka P;Petrini JHJ;Revy P
• 通讯作者: Revy P