Studying the mechanisms underlying the protection of common fragile sites and structure-prone DNA sequences

研究保护常见脆弱位点和易于结构的 DNA 序列的机制

基本信息

批准号：
10652454
负责人：
Xiaohua Wu
金额：
$ 40.17万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10652454
关键词：
AT Rich Sequence ATRX gene Abbreviations Address Aphidicolin Applications Grants Cells Chromatin Remodeling Factor Chromosomal Rearrangement Chromosome Fragile Sites Chromosome Structures Chromosomes Colon Carcinoma Colonic Neoplasms Complex DAXX gene DNA DNA Sequence DNA Single Strand Break DNA biosynthesis DNA replication fork Deposition Development Double Strand Break Repair ERCC1 gene Exhibits Foundations G-Quartets Gene Conversion Genome Stability Human Genome MSH2 gene MSH3 gene Maintenance Malignant Neoplasms Mammalian Cell Mediating Metaphase Mismatch Repair Mismatch Repair Deficiency Mitotic Mitotic Recombination Modeling Molecular Molecular Chaperones Mus Pathway interactions Polyacrylamide Gel Electrophoresis Principal Investigator Proteins RAS genes Reporter Resistance Role Structure Testing Work cancer therapy chemotherapy chromatin immunoprecipitation chromatin remodeling genome-wide homologous recombination hydroxyurea insight neoplastic cell novel novel therapeutic intervention preservation prevent programs replication stress synthetic lethal interaction targeted treatment telomere translocase treatment strategy tumor tumor xenograft

项目摘要

Principal Investigator: Wu, Xiaohua Project Summary Studying the mechanisms underlying the protection of common fragile sites and structure- prone DNA sequences Project Summary/Abstract Common fragile sites (CFSs) are large chromosomal regions that often exhibit gaps and breaks on metaphase chromosomes upon replication stress. Structure-prone AT-rich sequences present at CFSs (CFS-ATs) contribute to CFS instability. Besides CFS-ATs, other structure-prone DNA sequences, such as G-quadruplexes (G4s), are also abundant in the human genome and are associated with chromosomal rearrangement breakpoints in cancer. Since CFSs and many structure-prone DNA sequences, including G4s, are part of normal chromosomal structures, it is important to understand how the integrity of these structure-prone DNA sequences is maintained in mammalian cells. In this grant application, we will use EGFP-based DSB repair reporters to investigate the mechanisms underlying the protection of structure-prone DNA sequences present at CFSs and G4s. We will study the role of chromatin-remodeling in the maintenance of CFSs and address the DSB repair mechanism specifically used to repair DSBs arising at DNA secondary structures upon fork collapse. We will also explore the functional coordination of pathways involved in protecting structure-prone DNA sequences from DSB formation and in repairing DSBs generated upon fork collapse at structure-prone DNA sequences. Furthermore, we will study how mismatch repair (MMR) proteins help preserve the integrity of structure-prone DNA sequences. Our studies will yield molecular insights into the mechanisms underlying the maintenance of the integrity of CFS and other structure-prone DNA sequences. These studies will also lay the groundwork for development of new targeted cancer treatment strategies.

首席研究员：吴，小乌亚项目摘要研究保护常见位点和结构的保护的基础机制俯卧的DNA序列项目摘要/摘要常见的脆弱部位（CFS）是大型染色体区域，经常表现出差距和复制应激时断裂中期染色体。易于结构的富含富含结构的序列 CFSS（CFS-ATS）的存在导致CFS不稳定性。除了CFS-ATS，其他结构易于 DNA序列（例如G-四链体（G4））在人基因组中也很丰富，并且是与癌症中的染色体重排断点有关。由于CFSS和许多容易结构的DNA序列（包括G4S）是正常染色体结构的一部分，它是重要的是要了解这些易于结构的DNA序列的完整性哺乳动物细胞。在此赠款应用程序中，我们将使用基于EGFP的DSB维修记者来研究存在的易于结构的DNA序列的机制 CFSS和G4S。我们将研究染色质复制在维持CFS和探讨专门用于修复DNA次级出现的DSB的DSB修复机制叉子倒塌后的结构。我们还将探索所涉及的途径的功能协调在保护易于结构的DNA序列免受DSB形成和修复DSB的过程中叉子在结构易发的DNA序列下塌陷。此外，我们将研究如何不匹配修复（MMR）蛋白有助于保留易于结构的DNA序列的完整性。我们的研究将产生对CFS完整性维持基础机制的分子见解和其他易于结构的DNA序列。这些研究还将为制定新的目标癌症治疗策略。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DNA repair protein RAD52 is required for protecting G-quadruplexes in mammalian cells.

DOI：
10.1016/j.jbc.2022.102770
发表时间：
2023-01
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Liu, Shuo;Wang, Zi;Shah, Sameer Bikram;Chang, Chia-Yu;Ai, Michael;Nguyen, Tran;Xiang, Rong;Wu, Xiaohua
通讯作者：
Wu, Xiaohua

Break-induced replication mechanisms in yeast and mammals.

DOI：
10.1016/j.gde.2021.08.002
发表时间：
2021-12
期刊：
CURRENT OPINION IN GENETICS & DEVELOPMENT
影响因子：
4
作者：
Wu, Xiaohua;Malkova, Anna
通讯作者：
Malkova, Anna

The Protexin complex counters resection on stalled forks to promote homologous recombination and crosslink repair.

DOI：
10.1016/j.molcel.2021.09.008
发表时间：
2021-11-04
期刊：
Molecular cell
影响因子：
16
作者：
Adeyemi RO;Willis NA;Elia AEH;Clairmont C;Li S;Wu X;D'Andrea AD;Scully R;Elledge SJ
通讯作者：
Elledge SJ

The concerted roles of FANCM and Rad52 in the protection of common fragile sites.

DOI：
10.1038/s41467-018-05066-y
发表时间：
2018-07-18
期刊：
Nature communications
影响因子：
16.6
作者：
Wang H;Li S;Oaks J;Ren J;Li L;Wu X
通讯作者：
Wu X

Cyclin E deregulation promotes loss of specific genomic regions.

DOI：
10.1016/j.cub.2015.03.022
发表时间：
2015-05-18
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Teixeira, Leonardo K.;Wang, Xianlong;Li, Yongjiang;Ekholm-Reed, Susanna;Wu, Xiaohua;Wang, Pei;Reed, Steven I.
通讯作者：
Reed, Steven I.