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

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。因为接受者 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-GlcNAc酰化是一种 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。

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.