USP1-dependent nucleolytic expansion of PRIMPOL-generated nascent DNA strand discontinuities during replication stress

生物 基因组不稳定性 DNA复制 DNA损伤 细胞生物学 泛素 DNA DNA修复 DNA再复制 复制蛋白A 遗传学 染色体复制控制 基因 DNA结合蛋白 转录因子
作者
Alexandra Nusawardhana,Lindsey M Pale,Claudia M. Nicolae,George‐Lucian Moldovan
出处
期刊:Nucleic Acids Research [Oxford University Press]
标识
DOI:10.1093/nar/gkad1237
摘要

Abstract DNA replication stress-induced fork arrest represents a significant threat to genomic integrity. One major mechanism of replication restart involves repriming downstream of the arrested fork by PRIMPOL, leaving behind a single-stranded DNA (ssDNA) gap. Accumulation of nascent strand ssDNA gaps has emerged as a possible determinant of the cellular hypersensitivity to genotoxic agents in certain genetic backgrounds such as BRCA deficiency, but how gaps are converted into cytotoxic structures is still unclear. Here, we investigate the processing of PRIMPOL-dependent ssDNA gaps upon replication stress induced by hydroxyurea and cisplatin. We show that gaps generated in PRIMPOL-overexpressing cells are expanded in the 3′-5′ direction by the MRE11 exonuclease, and in the 5′-3′ direction by the EXO1 exonuclease. This bidirectional exonucleolytic gap expansion ultimately promotes their conversion into DSBs. We moreover identify the de-ubiquitinating enzyme USP1 as a critical regulator of PRIMPOL-generated ssDNA gaps. USP1 promotes gap accumulation during S-phase, and their expansion by the MRE11 and EXO1 nucleases. This activity of USP1 is linked to its role in de-ubiquitinating PCNA, suggesting that PCNA ubiquitination prevents gap accumulation during replication. Finally, we show that USP1 depletion suppresses DSB formation in PRIMPOL-overexpressing cells, highlighting an unexpected role for USP1 in promoting genomic instability under these conditions.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
1秒前
2秒前
3秒前
7秒前
tu发布了新的文献求助10
8秒前
彭于晏应助高大的一曲采纳,获得10
10秒前
高高高完成签到,获得积分20
11秒前
12秒前
尽如完成签到,获得积分10
14秒前
陈宝妮完成签到,获得积分10
17秒前
17秒前
18秒前
大气的曼文完成签到 ,获得积分20
18秒前
石狗西完成签到 ,获得积分10
18秒前
19秒前
jia发布了新的文献求助10
19秒前
无明怀雪完成签到,获得积分20
19秒前
Choi发布了新的文献求助10
20秒前
21秒前
tu完成签到,获得积分10
21秒前
Jolleyhaha完成签到 ,获得积分10
22秒前
cy发布了新的文献求助10
22秒前
24秒前
tao1225发布了新的文献求助10
25秒前
krismelo发布了新的文献求助10
25秒前
机灵海之完成签到 ,获得积分10
25秒前
sadascaqwqw发布了新的文献求助10
27秒前
Solar energy发布了新的文献求助10
28秒前
林薯条应助严小之采纳,获得10
29秒前
30秒前
cy完成签到,获得积分10
31秒前
krismelo完成签到,获得积分10
36秒前
psj完成签到,获得积分10
36秒前
37秒前
37秒前
pluto应助科研通管家采纳,获得10
37秒前
赘婿应助科研通管家采纳,获得10
37秒前
科研通AI2S应助科研通管家采纳,获得30
37秒前
orixero应助科研通管家采纳,获得30
38秒前
高分求助中
Evolution 10000
Becoming: An Introduction to Jung's Concept of Individuation 600
Ore genesis in the Zambian Copperbelt with particular reference to the northern sector of the Chambishi basin 500
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
A new species of Velataspis (Hemiptera Coccoidea Diaspididae) from tea in Assam 500
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 500
The Kinetic Nitration and Basicity of 1,2,4-Triazol-5-ones 440
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3164337
求助须知:如何正确求助?哪些是违规求助? 2815164
关于积分的说明 7907823
捐赠科研通 2474743
什么是DOI,文献DOI怎么找? 1317626
科研通“疑难数据库(出版商)”最低求助积分说明 631898
版权声明 602234