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.

在原代人或小鼠成纤维细胞中，双链断裂（DSB）是最危险的DNA病变之一，估计每天每天每天10次发生率。这些天然存在的DSB是在失速的DNA复制叉崩溃，跨划痕的复制，内源性起源的活性氧或DNA核酸内切酶的不合时宜的作用时产生的。 DSB主要通过非同源末端连接（NHEJ）和同源重组（HR）修复。 NHEJ是主要途径，在整个细胞周期中都使用，而HR则在S/G2阶段活跃，在S/G2阶段，姐妹染色单体可作为修复模板可用。 DSB修复途径选择的调节对我们的细胞非常重要，因为DSB修复途径中的错误会产生基因重排，而DSB修复错误通常会产生杀死细胞的异常染色体结构。 NHEJ仅在最小处理的DNA末端处于活动状态。 DNA末端切除抑制了它，而5'-3'核降解产生单链DNA（ssDNA）的过程。 3'-ssDNA悬垂物立即被复制蛋白A（RPA）蛋白复合物（由〜70、32和14 kDa组成，分别称为RPA70，RPA32和RPA14），以保护保护。涂有RPA的ssDNA是所有HR子街道的重要中间体。 CTBP相互作用蛋白（CTIP）是控制DNA末端切除的关键DNA内切酶。 CTIP由多种翻译后修饰（PTM）靶向，包括磷酸化，泛素化，乙酰化和其他鲜为人知的修饰。