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RECQ5-dependent SUMO2 conjugation of PCNA in the resolution of transcription-replication conflicts

PCNA 的 RECQ5 依赖性 SUMO2 缀合解决转录复制冲突

基本信息

批准号：
10328909
负责人：
Yilun Liu
金额：
$ 38.78万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328909
关键词：
Biological Assay Biology Bypass Cell Death Cells Chromatin Chromosome Fragile Sites Complex Conflict (Psychology)DNA DNA Damage DNA Double Strand Break DNA Sequence Rearrangement DNA biosynthesis DNA lesion DNA replication fork DNA-Directed DNA Polymerase Data Defect Deposition Event Fractionation Frequencies Genes Genetic Transcription Genomic Instability Goals Hematopoietic Neoplasms Histones Human In Vitro Knockout Mice Lead Link Lysine Malignant Neoplasms Mediating Metabolic Modeling Modification Molecular Molecular Chaperones Neoplastic Cell Transformation Pathogenesis Proliferating Cell Nuclear Antigen Proteins Proteomics Publishing RECQL5 gene RNA RNA Polymerase II Resolution Risk Factors Role S phase Site Solid Neoplasm Source Sumoylation Pathway Transcriptional Regulation Tumor Suppressor Proteins Work Xenograft procedure base cancer cell cancer risk cancer type cell growth cell transformation conflict resolution helicase homologous recombination in vitro Assay innovation member mouse model novel prevent recruit response transcriptome ubiquitin-protein ligase

项目摘要

Project Summary Proliferating cell nuclear antigen (PCNA) is an essential component of the replisome, and it enhances the processivity of the DNA polymerases in DNA synthesis. In addition, in response to DNA damage, PCNA is ubiquitinated at lysine 164 (K164) to bypass DNA lesions. In unperturbed cells, the same K164 residue can also be conjugated with either SUMO1 or SUMO2, and SUMO1-PCNA has been implicated in recruiting PARI helicase to suppress homologous recombination. However, the source of replication obstacle that triggers PCNA SUMOylation is yet to be defined, and the regulators of PCNA SUMOylation are not known. It is also not clear if SUMO2-PCNA functions redundantly to SUMO1-PCNA. Our newly published data argue that human SUMO2-PCNA has a unique function in transcription that is not shared by SUMO1-PCNA, because only SUMO2-PCNA is associated with transcriptionally active chromatin. Even though PCNA SUMO2 conjugation occurs in S-phase, SUMO2-PCNA is induced by RNA polymerase II - dependent transcription and requires the RNA polymerase II - interacting protein, RECQ5 DNA helicase. Importantly, cells with reduced SUMO2-PCNA accumulate transcription-induced DNA double-strand breaks during S-phase. Therefore, our data support a conceptually innovative model for a role of SUMO2-PCNA in resolving transcription-replication conflicts to minimize genomic instability. The goal of this proposal is (1) to identify the molecular factors that facilitate the transcription-induced SUMO2 conjugation of PCNA, (2) to identify the molecular mechanism by which SUMO2- PCNA resolves transcription-replication conflicts, and (3) to elucidate the contribution of SUMO2-PCNA toward preventing genomic instability and neoplastic transformation, as transcription-replication conflicts are major source for common fragile site instability.

项目总结