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Coordination of ATR Signaling for Genetic Quality Control, Silencing, and DNA Repair During Meiosis

减数分裂期间遗传质量控制、沉默和 DNA 修复的 ATR 信号协调

基本信息

批准号：
10413949
负责人：
Marcus Smolka
金额：
$ 41.93万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-13 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10413949
关键词：
ATR checkpoint CHEK1 gene CHEK2 gene Cell Death Cells Chromatin Chromosome Pairing Chromosomes Clinical Closure by clamp Complement Complex Congenital Abnormality DNA DNA Damage DNA Repair Defect Development Double Strand Break Repair Ensure Event Failure Gene Silencing Generations Genetic Genetic Determinism Genome Germ Cells Goals Growth Haploidy Infertility Knowledge Lead Maintenance Malignant Neoplasms Mammals Mass Spectrum Analysis Mediating Meiosis Meiotic Prophase I Mitotic Molecular Monitor Mus Mutant Strains Mice Mutation Oocytes Output Pathway interactions Phenotype Phosphotransferases Process Production Proteins Proteomics Quality Control RAD9A gene Regulation Reproduction Role Scaffolding Protein Signal Transduction Somatic Cell Spermatocytes Spermatogenesis Structure TOPBP1 Gene Testis Time Work base cancer therapy experimental study genetic analysis genome editing innovation insight mouse model mutant novel paralogous gene phosphoproteomics prevent rational design recombinational repair repair function repaired response sex sperm cell virtual

项目摘要

Infertility and birth defects often arise due to improper genetic quality control during meiosis. To ensure the production of gametes without genetic defects, the genome of meiocytes is monitored by a set of evolutionarily conserved kinases, known as checkpoint kinases. These kinases sense damage to DNA or problems in chromosome pairing and, upon activation, can block meiotic progression and induce cell death. But the action of checkpoint kinases is not solely utilized as a quality control mechanism. Programmed double strand break (DSB) formation is an abundant and essential event for normal meiotic progression, and checkpoint kinases are required to coordinate key events in recombination repair, crossover regulation and transcriptional silencing. How meiotic checkpoint signaling is regulated is not understood, especially in mammals. In particular, little is known about how checkpoint kinases can act both as essential regulators of normal meiotic progression as well as effectors of quality control mechanisms that lead to cell death. This knowledge gap poses a major barrier for understanding the determinants of genetic quality control and how mis-regulation of checkpoint signaling may aberrantly block meiotic progression and promote infertility. The same pathways also mediate fundamental DNA repair and checkpoint functions in mitotic cells, are sometimes deregulated in cancers, and are being targeted clinically as an emerging strategy for cancer treatment. This proposal applies innovative approaches to overcome long-standing barriers for the study of meiotic checkpoint signaling in mammals. The proposed studies focus on the essential checkpoint kinase ATR, which is important for DSB repair and transcriptional silencing of unsynapsed chromatin during meiosis and is regulated in part by the scaffolding protein TOPBP1 and other upstream regulators such as the RAD9A-RAD1-HUS1 complex. Cutting edge approaches for genome editing in the mouse will be used to generate rationally designed separation-of- function mouse mutants with the goal of revealing novel checkpoint regulatory mechanisms operative in meiosis. To guide and complement genetic and functional experiments, mass spectrometry analysis of testis extracts will be used for quantitative and unbiased characterization of checkpoint signaling in spermatocytes. Collectively, these studies are expected to reveal how meiotic ATR signaling is coordinated to achieve structure-specific signaling outputs in response to unrepaired DSBs or chromosome asynapsis, without inducing cell death. Beyond providing fundamental insights into the actions of genome maintenance pathways that function in virtually all cells, the results from this work will carry important implications related to the molecular origins of infertility and birth defects as well as the impact of ATR inhibition in clinical settings.

不育症和出生缺陷往往是由于减数分裂期间遗传质量控制不当而引起的。为了确保配子的产生没有遗传缺陷，性母细胞的基因组由一组进化上保守的激酶（称为检查点激酶）监控。这些激酶检测DNA损伤或染色体配对问题，激活后可阻断减数分裂进程并诱导细胞死亡。但是检查点激酶的作用并不仅仅被用作质量控制机制。程序性双链断裂（DSB）的形成是正常减数分裂进程中丰富且必需的事件，并且需要检查点激酶来协调重组修复、交叉调节和转录沉默中的关键事件。减数分裂检查点信号是如何调节的还不清楚，特别是在哺乳动物中。特别是，很少有人知道检查点激酶如何既可以作为正常减数分裂进程的重要调控因子，也可以作为导致细胞死亡的质量控制机制的效应子。这一知识缺口构成了理解遗传质量控制的决定因素以及检查点信号传导的错误调节如何异常地阻断减数分裂进程并促进不育的主要障碍。相同的途径也介导有丝分裂细胞中的基本DNA修复和检查点功能，有时在癌症中被解除管制，并且在临床上被靶向作为癌症治疗的新兴策略。该提案采用创新方法来克服哺乳动物减数分裂检查点信号研究的长期障碍。拟议的研究集中在必需的检查点激酶ATR，这是重要的DSB修复和转录沉默的未突触的染色质在减数分裂过程中，部分是由支架蛋白TOPBP 1和其他上游调控因子，如RAD 9A-RAD 1-HUS 1复合物。用于小鼠基因组编辑的尖端方法将用于产生合理设计的功能分离小鼠突变体，目的是揭示在减数分裂中起作用的新的检查点调控机制。为了指导和补充遗传和功能实验，睾丸提取物的质谱分析将用于精母细胞中检查点信号传导的定量和无偏表征。总的来说，这些研究预计将揭示如何协调减数分裂ATR信号，以实现结构特异性信号输出响应未修复的DSB或染色体不联会，而不诱导细胞死亡。除了对几乎所有细胞中发挥作用的基因组维持途径的作用提供基本见解外，这项工作的结果将对不孕症和出生缺陷的分子起源以及ATR抑制在临床环境中的影响产生重要影响。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ATR signaling in mammalian meiosis: From upstream scaffolds to downstream signaling.

哺乳动物减数分裂中的ATR信号传导：从上游支架到下游信号传导。

DOI：
10.1002/em.22401
发表时间：
2020-08
期刊：
Environmental and molecular mutagenesis
影响因子：
2.8
作者：
Pereira C;Smolka MB;Weiss RS;Brieño-Enríquez MA
通讯作者：
Brieño-Enríquez MA

The DNA helicase FANCJ (BRIP1) functions in Double Strand Break repair processing, but not crossover formation during Prophase I of meiosis in male mice.

DNA 解旋酶 FANCJ (BRIP1) 在雄性小鼠减数分裂前期 I 期间的双链断裂修复过程中起作用，但在交叉形成中不起作用。

DOI：
10.1101/2023.10.06.561296
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Horan,TeganS;Ascenção,CarollineFR;Mellor,ChristopherA;Wang,Meng;Smolka,MarcusB;Cohen,PaulaE
通讯作者：
Cohen,PaulaE