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The role of O-GlcNAcylation in DNA damage repair and cancer therapy

O-GlcNAcylation 在 DNA 损伤修复和癌症治疗中的作用

基本信息

批准号：
10171810
负责人：
Jeremy Michael Stark
金额：
$ 39.57万
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：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171810
关键词：
Abbreviations Animal Cancer Model BRCA1 gene BRCA2 gene Biological Process Cell Cycle Arrest Cell Cycle Progression Cells DNA Damage DNA Double Strand Break DNA Repair DNA lesion Defect Double Strand Break Repair Enzymes Event Excision Future Genetic Engineering Impairment Ionizing radiation Lead Lesion Link Malignant Neoplasms Maps Mediating Molecular O-GlcNAc transferase Phosphorylation Phosphorylation Site Play Post-Translational Protein Processing Proteins Radiation Induced DNA Damage Radiation induced double strand break Radiation therapy Research Research Project Grants Research Proposals Role Serine Signal Transduction Site Testing Therapeutic Threonine UDP-glucosamine Ubiquitination brca gene cancer therapy cell growth design efficacy evaluation experimental study in vivo inhibitor/antagonist neoplastic cell novel strategies novel therapeutic intervention peptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidase recruit repaired response therapeutically effective tumor

项目摘要

Project Summary/Abstract O-linked N-acetyglucosaminylation (O-GlcNAcylation) is a reversible posttranslational modification that plays a key role in ionizing radiation (IR)-induced DNA damage response. O-GlcNAcylation is catalyzed by O- GlcNActransferase (OGT), which transfers N-acetyl-D-glucosamine from UDP-GlcNAc to serine or threonine residues of proteins. This posttranslational modification is also removed by O-GlcNAcase (OGA). In our studies, we have shown that O-GlcNAcylation is significantly enriched at DNA lesions. Since the acceptors of O-GlcNAcylation are serine or threonine residues, O-GlcNAcylation competes with DNA damage-induced phosphorylation, which in turn regulates DNA damage repair. Thus, we hypothesize that O-GlcNAcylation is a key molecular event in response to IR treatment, and targeting O-GlcNAcylation can be an effective therapeutic strategy to cancer treatment. In this research proposal, we plan to focus on one major O-GlcNAcylation substrate MDC1, and examine the role of O-GlcNAcylated MDC1 in DNA damage response including the phosphorylation events on MDC1, MDC1 governed protein ubiquitination cascade, and DNA double-strand break repair. Using O-GlcNAcylated MDC1 as the readouts, we will analyze the biological functions of both OGT and OGA in IR-induced DNA damage repair, and explore the inhibition of OGA as a novel therapeutic strategy to treat BRCA1 or BRCA2- deficient tumors in vivo.

项目总结/文摘