Processing and Repair of DNA Crosslinks

DNA 交联的加工和修复

基本信息

批准号：
10333383
负责人：
RICHARD D WOOD
金额：
$ 180.56万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-10 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10333383
关键词：
Biochemical Biochemistry Bypass Cancer Etiology Carmustine Cell Cycle Cells Cellular biology Chlorambucil Cisplatin Complex Core Facility DNA DNA Binding DNA Damage DNA Repair DNA Repair Gene DNA biosynthesis DNA crosslink DNA replication fork DNA-Binding Proteins DNA-protein crosslink Defect Fanconi Anemia pathway Fanconi&apos s Anemia Future Gene Expression Genetic Genome Goals HMGB1 gene HMGB2 gene HMGB3 gene Individual Investigation Knowledge Lesion MSH2 gene MSH3 gene Mechlorethamine Medical Melphalan Mitomycin C Modeling Molecular Mutagenesis Nitrosourea Compounds Pathway interactions Peptides Pharmaceutical Preparations Platinum Process Proteins Psoralens Research Personnel Research Project Grants Role Route Services Source Variant analog base biomarker development cancer therapy chemotherapeutic agent chemotherapy crosslink experimental study improved individual patient neoplastic cell novel nuclease prevent programs recruit repaired scaffold

项目摘要

PROJECT SUMMARY DNA crosslinks, including interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs) are forms of DNA damage that arise continuously in DNA from endogenous and natural sources. They must be removed in order to allow accurate genome duplication and gene expression. Many chemotherapeutic agents induce ICLs including nitrogen mustards and derivatives (melphalan, chlorambucil), psoralens, mitomycin C, platinum- based compounds such as cisplatin, and nitrosoureas such as BCNU. Identification and future development of biomarkers associated with ICL repair proficiency will facilitate precision medical treatment for individual patients. Despite the importance of crosslinks in cancer etiology and treatment, mechanisms of DNA crosslink repair are known only in outline, and many steps are simply assumed. An integrated, programmatic approach involving four Research Projects and two service Cores will conduct experimental investigations under the auspices of the Program and contribute, both individually and synergistically, to this theme. Each Overall Goal/Specific Aim is independently engaged by each project using distinct and complementary approaches. The Program Project is organized around three aims, representing goals of the project: Aim 1: Determine how different pathways of crosslink repair are used or coordinated. The program will investigate major gaps in knowledge about different crosslink repair pathways, including how nucleases or complexes/components are recruited and used in different situations, variations of crosslink repair during the cell cycle, action of crosslink repair at different configurations of model stalled replication forks, whether ICL repair differs for different lesions, and the mechanism of error-free and mutagenic crosslink repair. Aim 2: Understand functions of newly discovered and little-studied crosslink repair components. One block to progress in understanding repair of ICLs is that there are a group of components that are known to be involved in crosslink repair, but where mechanistic roles are unassigned or known only superficially. In this program the investigators will cooperate to determine their functions. Major unknown components include SLX4IP (which associates with SLX4); the HMGB1, HMGB2 and HMGB3 DNA binding proteins; the MSH2-MSH3 complex (which binds DNA distortions); and UHRF1 (postulated as an alternative scaffold for delivery of nucleases). Aim 3: Investigate the mechanisms of repair of DNA-protein crosslinks. There are likely to be several routes of DPC repair and tolerance. Experiments will be undertaken to determine different modes of processing. Major gaps in knowledge include the involvement of Fanconi anemia (FA) pathway proteins in repair and how features of FA might be explained by defects in DPC repair. We will investigate involvement of replicative bypass (translesion DNA synthesis) in tolerance of DNA-peptide crosslinks (modeling proteolytically processed DPCs). We will also explore pathways that prevent or induce mutagenesis by DPCs.

项目摘要 DNA交联，包括链间交联（ICL）和DNA-蛋白交联（DPC）是DNA的形式内源性和自然来源的DNA中不断产生的损害。它们必须按顺序删除允许准确的基因组重复和基因表达。许多化学治疗剂诱导ICL 包括氮芥末和衍生物（Melphalan，Chlorambucil），牛cor骨，丝裂霉素C，铂 - 基于顺铂和硝基库等基于BCNU的化合物。身份证明和未来发展与ICL维修能力相关的生物标志物将有助于个人的精确医疗患者。尽管交联在癌症的病因和治疗中很重要，但DNA交联的机制维修仅在大纲中知道，并且简单地假定了许多步骤。一种集成的程序化方法涉及四个研究项目和两个服务核心将在该程序的主持人对此主题进行了单独和协同的贡献。每个总体每个项目都使用不同的和互补的方法独立参与目标/特定目标。该计划项目围绕三个目标组织，代表了该项目的目标： AIM 1：确定如何使用或协调的交联维修路径不同。该程序将研究有关不同交联修复途径的知识的主要差距，包括核酸酶或如何招募和组件在不同的情况下招募和使用细胞周期，交联维修在模型停滞叉的不同配置上的作用，是否ICL是否ICL 维修的不同病变的不同，无错误和诱变交联的修复机理。目标2：了解新发现的和少量研究的交联维修组件的功能。一个街区理解ICL修复的进展是，有一组已知涉及的组件在交叉链接修复中，但在机械作用的情况下是未分配或仅在表面上知道的。在这个程序中调查人员将合作确定其功能。主要未知组件包括SLX4IP（其中与slx4相关的; HMGB1，HMGB2和HMGB3 DNA结合蛋白； MSH2-MSH3复合物（结合DNA失真）；和UHRF1（假定是核酸酶输送的替代支架）。 AIM 3：研究DNA蛋白交联的修复机制。可能有几条路线 DPC修复和耐受性。将进行实验以确定不同的处理模式。主要的知识的差距包括Fanconi贫血（FA）途径蛋白在维修中的参与以及如何 FA的功能可能通过DPC修复中的缺陷来解释。我们将调查复制的参与 DNA肽交联的耐受性（对蛋白水解的蛋白水解处理，绕过DNA合成） DPC）。我们还将探索预防或诱导DPC诱变的途径。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TDP1-independent pathways in the process and repair of TOP1-induced DNA damage.

DOI：
10.1038/s41467-022-31801-7
发表时间：
2022-07-22
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Zhang, Huimin;Xiong, Yun;Su, Dan;Wang, Chao;Srivastava, Mrinal;Tang, Mengfan;Feng, Xu;Huang, Min;Chen, Zhen;Chen, Junjie
通讯作者：
Chen, Junjie

FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells.