HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation.
HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation.
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HPF 1依赖性PARP激活促进LIG 3-XRCC 1介导的冈崎片段连接的备用途径
DOI：
10.1093/nar/gkab269
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发表时间：
2021-05-21
影响因子：
14.9
通讯作者：
Nakanishi M
中科院分区：
文献类型：
--
作者：
Kumamoto S;Nishiyama A;Chiba Y;Miyashita R;Konishi C;Azuma Y;Nakanishi M
DNA连接酶1 （LIG1）是负责冈崎片段连接的主要DNA连接酶。最近的研究表明，在LIG1不起作用的情况下，LIG3与XRCC1复合物作为冈崎片段连接的替代参与者，尽管潜在的机制在很大程度上是未知的。在这里，我们使用一种来自爪蟾卵提取物的无细胞系统，证明了PARP1-HPF1在lig3依赖性Okazaki片段连接中的重要作用。我们发现，即使在没有LIG1的情况下，Okazaki片段最终也会被连接，而LIG3-XRCC1则被招募到染色质上。同时，LIG1缺乏以parp1 - hpf1依赖的方式诱导组蛋白H3的adp核糖基化。PARP1或HPF1的缺失导致在染色质上募集LIG3的失败，以及随后在lig1缺失的提取物中冈崎片段连接的失败。重要的是，当LIG1和XRCC1共同耗尽时，冈崎片段根本没有结扎。我们的研究结果表明，一种独特形式的adp核糖基化信号传导促进了LIG3在染色质上的募集，并作为LIG1扰动的备份系统介导了冈崎片段连接。
DNA ligase 1 (LIG1) is known as the major DNA ligase responsible for Okazaki fragment joining. Recent studies have implicated LIG3 complexed with XRCC1 as an alternative player in Okazaki fragment joining in cases where LIG1 is not functional, although the underlying mechanisms are largely unknown. Here, using a cell-free system derived from Xenopus egg extracts, we demonstrated the essential role of PARP1-HPF1 in LIG3-dependent Okazaki fragment joining. We found that Okazaki fragments were eventually ligated even in the absence of LIG1, employing in its place LIG3-XRCC1, which was recruited onto chromatin. Concomitantly, LIG1 deficiency induces ADP-ribosylation of histone H3 in a PARP1-HPF1-dependent manner. The depletion of PARP1 or HPF1 resulted in a failure to recruit LIG3 onto chromatin and a subsequent failure in Okazaki fragment joining in LIG1-depleted extracts. Importantly, Okazaki fragments were not ligated at all when LIG1 and XRCC1 were co-depleted. Our results suggest that a unique form of ADP-ribosylation signaling promotes the recruitment of LIG3 on chromatin and its mediation of Okazaki fragment joining as a backup system for LIG1 perturbation.
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影响因子：
14.9
作者：
Hanzlikova H;Gittens W;Krejcikova K;Zeng Z;Caldecott KW
通讯作者：
Caldecott KW
影响因子：
14.9
作者：
Fan, JS;Otterlei, M;Wilson, DM
通讯作者：
Wilson, DM
影响因子：
16
作者：
Gibbs-Seymour I;Fontana P;Rack JGM;Ahel I
通讯作者：
Ahel I
影响因子：
5.3
作者：
CALDECOTT, KW;MCKEOWN, CK;THOMPSON, LH
通讯作者：
THOMPSON, LH
DOI：
10.1038/nrm.2017.53
发表时间：
2017-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Ray Chaudhuri A;Nussenzweig A
通讯作者：
Nussenzweig A