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

项目摘要/摘要 O-连接N-乙酰氨基葡萄糖基化(O-GlcNacylation)是一种可逆的翻译后修饰 在电离辐射(IR)诱导的DNA损伤反应中起着关键作用。O-GlcN酰化反应是由O- 谷氨酰转移酶(OGT)，将N-乙酰-D-氨基葡萄糖从UDP-GlcNAc转化为丝氨酸或苏氨酸 蛋白质残留物。这种翻译后修饰也被O-GlcNAcase(OGA)去除。在我们的 研究表明，O-GlcN酰化在DNA损伤处显著丰富。由于接受者是 O-GlcN酰化是丝氨酸或苏氨酸残基，O-GlcN酰化与DNA损伤竞争 磷酸化，进而调节DNA损伤修复。因此，我们假设O-GlcN酰化是一个 IR反应中的关键分子事件和靶向O-GlcN酰化可能是一种有效的 癌症治疗的治疗策略。 在这项研究计划中，我们计划专注于一种主要的O-GlcN酰化底物MDC1，并检查 O-GlcNacylated MDC1在DNA损伤反应中的作用，包括MDC1上的磷酸化事件 MDC1控制蛋白质泛素化级联和DNA双链断裂修复。使用O-GlcNacylated 作为读数，我们将分析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BRCA1或BRCA2的新策略- 体内缺陷性肿瘤。

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.