Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells.
Temporally distinct post-replicative repair mechanisms fill PRIMPOL-dependent ssDNA gaps in human cells.
复制标题
时间上不同的复制后修复机制填补了人类细胞中PRIMPOL依赖的ssDNA缺口。
DOI：
10.1016/j.molcel.2021.09.013
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发表时间：
2021-10-07
期刊：
影响因子：
16
通讯作者：
Vindigni A
中科院分区：
文献类型：
--
作者：
Tirman S;Quinet A;Wood M;Meroni A;Cybulla E;Jackson J;Pegoraro S;Simoneau A;Zou L;Vindigni A
PRIMPOL重现允许DNA复制跳过DNA损伤，导致ssDNA间隙。必须填补这些空白以保持基因组的稳定性。利用DNA纤维方法直接监测间隙填充，我们研究了在顺铂处理的细胞中，当PRIMPOL表达增加或由于SMARCAL1失活或PARP抑制导致复制叉逆转缺陷时，填充ssDNA间隙的复制后机制。我们发现依赖于E3泛素连接酶RAD18、PCNA单泛素化、REV1和POLζ翻译合成聚合酶的机制促进了G2的间隙填充。E2偶联酶UBC13， RAD51重组酶和REV1-POLζ负责S中的间隙填充，这表明在整个细胞周期中，间隙填充的时间不同途径起作用。此外，我们发现BRCA1和BRCA2通过限制MRE11活性来促进间隙填充，同时靶向分叉逆转和间隙填充增强了brca缺陷细胞的化学敏感性。PRIMPOL会产生ssDNA缺口，必须填补这些缺口才能维持基因组的稳定。Tirman等人的研究表明，在人类细胞的整个细胞周期中，有两种不同的途径填补ssDNA的空缺，而BRCA蛋白通过限制MRE11的活性来促进空缺的填补。这些通路的破坏增强了基因组的不稳定性和化学敏感性。
PRIMPOL repriming allows DNA replication to skip DNA lesions, leading to ssDNA gaps. These gaps must be filled to preserve genome stability. Using a DNA fiber approach to directly monitor gap filling, we studied the post-replicative mechanisms that fill the ssDNA gaps generated in cisplatin-treated cells upon increased PRIMPOL expression or when replication fork reversal is defective because of SMARCAL1 inactivation or PARP inhibition. We found that a mechanism dependent on the E3 ubiquitin ligase RAD18, PCNA monoubiquitination, and the REV1 and POLζ translesion synthesis polymerases promotes gap filling in G2. The E2 conjugating enzyme UBC13, the RAD51 recombinase, and REV1-POLζ are instead responsible for gap filling in S, suggesting that temporally distinct pathways of gap filling operate throughout the cell cycle. Furthermore, we found that BRCA1 and BRCA2 promote gap filling by limiting MRE11 activity and that simultaneously targeting fork reversal and gap filling enhances chemosensitivity in BRCA-deficient cells. PRIMPOL generates ssDNA gaps, which must be filled to maintain genome stability. Tirman et al. show that two distinct pathways fill ssDNA gaps throughout the cell cycle in human cells and that BRCA proteins promote gap filling by limiting MRE11 activity. Disruption of these pathways enhances genome instability and chemosensitivity.
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影响因子：
16
作者：
Bianchi, Julie;Rudd, Sean G.;Jozwiakowski, Stanislaw K.;Bailey, Laura J.;Soura, Violetta;Taylor, Elaine;Stevanovic, Irena;Green, Andrew J.;Stracker, Travis H.;Lindsay, Howard D.;Doherty, Aidan J.
通讯作者：
Doherty, Aidan J.
影响因子：
16.8
作者：
Berti, Matteo;Chaudhuri, Arnab Ray;Thangavel, Saravanabhavan;Gomathinayagam, Shivasankari;Kenig, Sasa;Vujanovic, Marko;Odreman, Federico;Glatter, Timo;Graziano, Simona;Mendoza-Maldonado, Ramiro;Marino, Francesca;Lucic, Bojana;Biasin, Valentina;Gstaiger, Matthias;Aebersold, Ruedi;Sidorova, Julia M.;Monnat, Raymond J., Jr.;Lopes, Massimo;Vindigni, Alessandro
通讯作者：
Vindigni, Alessandro
影响因子：
14.9
作者：
Diamant N;Hendel A;Vered I;Carell T;Reissner T;de Wind N;Geacinov N;Livneh Z
通讯作者：
Livneh Z
影响因子：
16
作者：
Berdichevsky, A;Izhar, L;Livneh, Z
通讯作者：
Livneh, Z
影响因子：
3.8
作者：
Branzei D;Szakal B
通讯作者：
Szakal B