R-loop的调控及其生理功能  

Functions and Regulations of R-loop

作　　者：张译匀 叶素敏 金建平 ZHANG Yiyun;YE Sumin;JIN Jianping(Life Sciences Institute,Zhejiang University,Hangzhou 310058,China;Center for Life Sciences,Shaoxing Institute,Zhejiang University,Shaoxing 321000,China;Cancer Center,Zhejiang University,Hangzhou 310058,China)

机构地区：[1]浙江大学生命科学研究院,杭州310058 [2]浙江大学绍兴研究院生命科学分中心,绍兴321000 [3]浙江大学癌症中心,杭州310058

出　　处：《生物化学与生物物理进展》2023年第5期1099-1109,共11页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(32150014,31970734);国家重点研发计划(2022YFC3401500);中央高校基本业务费资助项目。

摘　　要：R环(R-loop)是一种DNA∶RNA杂合链(DNA∶RNA hybrids),由一条RNA单链侵入双链DNA,与其中一条DNA模板链结合,从而释放出一条DNA单链而产生。R-loop在细胞生命活动中扮演着重要角色,与基因组稳定性、转录调控,以及表观修饰等重要生物学过程有着密不可分的关系。很多因素参与对R-loop的调控,例如RNA转录和加工、染色体的修饰、DNA损伤反应等;同时,许多酶蛋白,如核糖核酸酶、解旋酶和拓扑异构酶等也参与调节细胞内的R-loop水平。了解R-loop的调控机制及其生物学功能有助于更好地理解基因组稳定性的维持机制,为治疗骨髓增生异常综合征、白血病、乳腺癌、前列腺癌等疾病开拓新思路。R-loops are formed during transcription when the nascent RNA generated by RNA polymerases hybridizes with its complementary DNA template,giving rise to a region of DNA∶RNA hybrid and a displaced single-stranded DNA.R-loops are stable structures that have important beneficial physiological functions,but also could pose a threat to genomic stability.Unscheduled R-loops induce cell cycle checkpoint activation,DNA damage,and chromosome rearrangement in mammalian cells.R-loops expose unstable single-stranded DNA,which is prone to transcription-related mutations and recombination.R-loops may also directly block DNA replication,leading to DNA double strand breaks.Abnormal accumulations of R-loops have been found in some syndromes,human neurological disorders,and cancers.On the other hand,R-loops also play positive roles in physiological processes,such as epigenetic modification,DNA repair,gene regulation and mitochondrial stability.R-loops forming on transcription-termination regions,promote RNA polymerase pausing before termination.R-loops are regulated delicately in cells.Collisions between replication and transcription cause accumulation of R-loops.Replication stress,DNA damage and RNA Pol II pausing also induce R-loop formation.To resolve R-loops when they form,cell evolve numerous dissolution mechanisms.Ribonuclease RNase H1 and RNase H2 bind to R-loops and then catalyze the cleavage of RNA.Helicases,such as SETX,DHX9,DDX21,unwind the RNA from the R-loops.Defects in RNA processing factors,chromatin modulators,DNA repair proteins,cause accumulation of R-loops,suggesting they are involved in R-loop regulations.To detect R-loops,several methods have been developed and are mainly based on the S9.6 antibody and the HBD domain of RNase H1,however,both of them possess some issues.Understanding the regulatory mechanisms of R-loop formation and clearance could help us better know how cells maintain genomic stability and prevent disease development.In this review article,we summarized functions and regulations of R-loops.W

关 键 词：R环 DNA∶RNA杂合链 基因组稳定性 转录 DNA损伤反应 

分 类 号：Q52[生物学—生物化学] Q74