Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability

RPA 和 RAD51 维持基因组稳定性的分子调节剂

• 批准号: 10541201
• 负责人: Weihang Chai
• 金额: $ 32.92万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541201
• 关键词: Affinity; Aging; BRCA mutations; BRCA2 gene; Binding; Binding Proteins; Biochemical; Biological; CRISPR/Cas technology; Cell Cycle Checkpoint; Cells; Cellular Metabolic Process; ChIP-seq; Chromosome Breakage; Complex; DNA; DNA Damage; DNA Repair; DNA biosynthesis; DNA lesion; DNA replication fork; Data; Disease; Environmental Exposure; Equilibrium; Event; Failure; Fiber; Functional disorder; Genetic; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Human; Human Genome; Invaded; Knowledge; Learning; Link; Maintenance; Malignant Neoplasms; Mediating; Molecular; Mutagens; Mutation; PARP inhibition; Pathogenesis; Poly(ADP-ribose) Polymerase Inhibitor; Positioning Attribute; Proteins; Public Health; Rad51 recombinase; Recovery; Repetitive Sequence; Research; Role; SS DNA BP; Single-Stranded DNA; Site; Stress; Surface; System; Techniques; Testing; Therapeutic; Work; anti-cancer therapeutic; cancer type; carcinogenesis; cellular imaging; design; environmental agent; genome integrity; genome-wide; improved; innovation; insight; multidisciplinary; neoplastic cell; nervous system disorder; next generation sequencing; novel; novel strategies; preservation; prevent; protective pathway; protein complex; recruit; repaired; replication stress; response; targeted cancer therapy; tumorigenesis

DNA damage constitutes a major threat to genetic integrity, and has thus been implicated in the pathogenesis of cancer. Elucidating the mechanism safeguarding genome stability is important for understanding the mechanism underlying carcinogenesis. Genome integrity is constantly threatened by endogenous and exogenous agents arising from cellular metabolic processes as well as environmental exposure, many of which impede normal DNA replication and cause replication fork stalling. Stalled forks need to be properly repaired and rescued to prevent DNA lesions and genome instabilities that contribute to tumorigenesis. To repair and rescue stalled replication, a network of proteins regulating DNA damage response, DNA repair, replication, and cell cycle checkpoints are activated in response to stalled replication in order to stabilize and restart stalled forks. However, the mechanism underlying fork repair is poorly understood. Recent studies have revealed that the balance and dynamics of RAD51 and RPA at stalled forks are crucial for fork stabilization and restart. Yet how RAD51 and RPA activities are modulated remains largely elusive. Our recent findings suggest that the high-affinity single-stranded DNA binding protein complex known as CST may be a new modulator for RPA and RAD51 at GC-rich repetitive sequences in response to replication stress. The objective of this proposal is to understand the molecular relationship between CST, RAD51 and RPA in fork rescue, with the goal to provide novel insights into how cells counteract DNA damage caused by genotoxins. We propose to integrate advanced biochemical, cell biological, cell imaging, and next-gen sequencing techniques to examine how CST may regulate RPA binding at stalled sites and maintain fork progression and stability under stress (Aim 1), define how CST may modulate RAD51 activity at GC-rich stalled sites (Aim 2), and characterize the regulatory role of a surface-exposed region of CST in regulating RAD51 and RPA activities (Aim 3). Findings from the proposed research will provide novel information on the mechanism of genome stability maintenance of rescuing stalled replication and preserving genome stability.

DNA损伤是对遗传完整性的重大威胁，因此已被牵连到

项目成果

The Intrinsically Disordered Region in the Human STN1 OB-Fold Domain Is Important for Protecting Genome Stability.

• DOI: 10.3390/biology10100977
• 发表时间: 2021-09-28
• 期刊: Biology
• 影响因子: 4.2
• 作者: Chai W;Chastain M;Shiva O;Wang Y
• 通讯作者: Wang Y

Crosstalk between CST and RPA regulates RAD51 activity during replication stress.

• DOI: 10.1038/s41467-021-26624-x
• 发表时间: 2021-11-05
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Lei KH;Yang HL;Chang HY;Yeh HY;Nguyen DD;Lee TY;Lyu X;Chastain M;Chai W;Li HW;Chi P
• 通讯作者: Chi P

CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection.

• DOI: 10.1038/s41467-023-43685-2
• 发表时间: 2023-11-30
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Jaiswal, Rishi Kumar;Lei, Kai-Hang;Chastain, Megan;Wang, Yuan;Shiva, Olga;Li, Shan;You, Zhongsheng;Chi, Peter;Chai, Weihang
• 通讯作者: Chai, Weihang