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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：
10399545
负责人：
Jeremy Michael Stark
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：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10399545
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 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/摘要 O-连接的N-乙酰葡糖胺化（O-GlcNAc化）是一种可逆的翻译后修饰，在电离辐射（IR）诱导的DNA损伤反应中起关键作用。O-GlcNAc酰化由O- GlcNAc转移酶（OGT），将N-乙酰基-D-葡糖胺从UDP-GlcNAc转移至丝氨酸或苏氨酸蛋白质残基。这种翻译后修饰也被O-GlcNAcase（OGA）去除。在我们研究表明，O-GlcNAc酰化在DNA损伤处显著富集。自从的接受者 O-GlcNAcylation是丝氨酸或苏氨酸残基，O-GlcNAcylation与DNA损伤诱导的竞争磷酸化，这反过来又调节DNA损伤修复。因此，我们假设O-GlcNAcylation是一种响应IR治疗的关键分子事件，并且靶向O-GlcNAc化可以是有效的癌症治疗的治疗策略。在这项研究计划中，我们计划专注于一个主要的O-GlcNAc酰化底物MDC 1，并检查 O-GlcNAc酰化MDC 1在DNA损伤反应中的作用，包括MDC 1上的磷酸化事件， MDC 1调控蛋白质泛素化级联反应和DNA双链断裂修复。使用O-GlcNAc酰化以MDC 1为读数，分析OGT和OGA在IR诱导的DNA中的生物学功能损伤修复，并探索抑制OGA作为治疗BRCA 1或BRCA 2- 体内缺乏肿瘤。