DNA Damage & DNA Replication: a Complex Relationship

DNA损伤

基本信息

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
项目类别：
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

项目摘要

“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.

“这是来自父母奖的。没有变化。” 我们的总体目标是：i。定义ATM激活的机制 MRE11复合物； ii。定义MRE11复合物在DNA复制中的作用； iii。到定义MRE11复合物在DNA复制应力响应的作用。作为一部分 DNA复制压力的重点是，我们的重点包括RTEL1 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。我们的这些主题的先前工作导致了有关科学进步和洞察力与人类健康相关的过程。特定的查询领域是：酵母中的遗传筛选和癌症基因组数据的挖掘揭示了分离功能RAD50突变的影响依赖ATM的DNA损伤信号传导不影响MRE11复合物的DNA修复功能。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确认是ATM激活的肌莫尔，但精通DNA修复。这些动物模型提供了一个独特的机会来描述MRE11复合物 - 依赖的ATM功能。我们已经确定了以某种方式在DNA复制叉处发挥作用的因素这取决于MRE11复合物。我们实验室的一个重要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，因此了解这个基本过程是我们工作的重要优先事项。而MRE11复合物在复制叉处的功能，RTEL1是一个促进远程DNA准确复制的解旋酶。我们有发现RTEL1会影响长期非的抽象和处置编码RNA，称为Terra，是从subtelomeric区域转录的所有真核生物。我们在工作的这一方面的目标是两倍。首先，到了解RTEL1在保持端粒稳定性中的作用。第二，使用这些信息阐明了Terra的功能，这是一个长期的问题。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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