The role of small ubiquitin-like modifier (SUMO) in DNA end resection

小泛素样修饰剂 (SUMO) 在 DNA 末端切除中的作用

• 批准号: RGPIN-2017-05752
• 负责人: Ismail, Ismail
• 金额: $ 1.89万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629629
• 关键词: role; small; ubiquitin; like; modifier

Double-strand breaks (DSBs), which are among the most dangerous DNA lesions, are estimated to occur at a rate of ten per cell per day in primary human or mouse fibroblasts. These naturally occurring DSBs are generated upon collapse of stalled DNA replication forks, replication across nicks, reactive oxygen species of endogenous origin or the untimely action of DNA endonucleases. DSBs are mainly repaired by non-homologous end joining (NHEJ) and homologous recombination (HR). NHEJ is the primary pathway and is used throughout the cell cycle, while HR is active in S/G2 phases where sister chromatids are available as repair templates. The regulation of DSB repair pathway choice is of great importance to our cells since errors in the choice of DSB repair pathway can create gene rearrangements and faulty DSB repair often generates aberrant chromosomal structures that kill cells. NHEJ is active only on minimally processed DNA ends; it is inhibited by DNA end resection, the process by which 5’-3’ nucleolytic degradation generates single-stranded DNA (ssDNA). The 3'-ssDNA overhangs are immediately coated by the Replication Protein A (RPA) protein complexes (composed of subunits of ~70, 32, and 14 kDa, referred as to RPA70, RPA32, and RPA14, respectively) for protection. The RPA-coated ssDNA is an essential intermediate of all HR sub-pathways. CtBP-interacting protein (CtIP) is a key DNA endonuclease controlling DNA end resection. CtIP is targeted by multiple posttranslational modifications (PTMs) including phosphorylation, ubiquityation, acetylation and other less known modifications.

双链断裂 (DSB) 是最危险的 DNA 损伤之一，估计在人类或小鼠原代成纤维细胞中每个细胞每天会发生 10 次双链断裂 (DSB) 这些自然发生的 DSB 是在停滞的 DNA 复制叉崩溃时产生的。 、跨切口复制、内源性活性氧或DNA核酸内切酶的不及时作用主要通过非同源末端连接（NHEJ）和同源重组来修复。 (HR) 是主要途径，在整个细胞周期中使用，而 HR 在 S/G2 阶段活跃，其中姐妹染色单体可用作修复模板。 DSB 修复途径选择的调节对我们的细胞非常重要。 DSB 修复途径的选择错误会导致基因重排，而错误的 DSB 修复通常会产生异常的染色体结构，从而杀死细胞。 5'-3' 溶核降解产生单链 DNA (ssDNA) 的过程。 3'-ssDNA 突出端立即被复制蛋白 A (RPA) 蛋白质复合物（由约 70、32 和 70 个亚基组成）覆盖。 14 kDa，分别称为 RPA70、RPA32 和 RPA14）用于保护 RPA 包被的 ssDNA 是必不可少的。 CtBP 相互作用蛋白 (CtIP) 是控制 DNA 末端切除的关键 DNA 核酸内切酶，是多种翻译后修饰 (PTM) 的靶标，包括磷酸化、泛素化、乙酰化和其他鲜为人知的修饰。