Human HELQ regulates DNA end resection at DNA double-strand breaks and stalled replication forks.
Human HELQ regulates DNA end resection at DNA double-strand breaks and stalled replication forks.
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DOI：
10.1093/nar/gkad940
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发表时间：
2023-12-11
影响因子：
14.9
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中科院分区：
文献类型：
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作者：
DNA双链断裂（DSB）后，几种核酸酶和解旋酶协同产生具有3′端游离末端的单链DNA（ssDNA），从而通过同源重组（HR）促进精确的DNA修复。相同的核酸酶可以作用于停滞的复制叉，促进新生DNA降解和叉不稳定性。有趣的是，一些HR因子，如CtIP和BRCA1，对这两个过程具有相反的调节作用，促进DSB的末端切除，但抑制停滞叉上新生DNA的降解。然而，为什么核酸酶的行动是由不同的机制，在两个DNA代谢调控的原因是知之甚少。我们表明，人类HELQ作为一个DNA末端切除调节剂，与其他监管机构看到的DSB和停滞叉上的DNA末端切除相反的活动。从机制上讲，HELQ解旋酶活性是EXO1介导的DSB末端切除所必需的，而HELQ的ssDNA结合能力是其招募到停滞的叉所必需的，促进叉保护并防止由复制应激引起的染色体畸变。在这里，HELQ与CtIP协同作用，但不与BRCA 1或BRCA 2协同作用，以保护失速的分叉。这些发现揭示了HELQ在调节DSB和停滞叉处的DNA末端切除中的意想不到的作用，这对于维持基因组稳定性是重要的。
Following a DNA double strand break (DSB), several nucleases and helicases coordinate to generate single-stranded DNA (ssDNA) with 3′ free ends, facilitating precise DNA repair by homologous recombination (HR). The same nucleases can act on stalled replication forks, promoting nascent DNA degradation and fork instability. Interestingly, some HR factors, such as CtIP and BRCA1, have opposite regulatory effects on the two processes, promoting end resection at DSB but inhibiting the degradation of nascent DNA on stalled forks. However, the reason why nuclease actions are regulated by different mechanisms in two DNA metabolism is poorly understood. We show that human HELQ acts as a DNA end resection regulator, with opposing activities on DNA end resection at DSBs and on stalled forks as seen for other regulators. Mechanistically, HELQ helicase activity is required for EXO1-mediated DSB end resection, while ssDNA-binding capacity of HELQ is required for its recruitment to stalled forks, facilitating fork protection and preventing chromosome aberrations caused by replication stress. Here, HELQ synergizes with CtIP but not BRCA1 or BRCA2 to protect stalled forks. These findings reveal an unanticipated role of HELQ in regulating DNA end resection at DSB and stalled forks, which is important for maintaining genome stability.
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影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
16.8
作者：
Bhat KP;Cortez D
通讯作者：
Cortez D
影响因子：
8.8
作者：
Cruz-Garcia, Andres;Lopez-Saavedra, Ana;Huertas, Pablo
通讯作者：
Huertas, Pablo
影响因子：
16.8
作者：
Buettner, Katharina;Nehring, Sebastian;Hopfner, Karl-Peter
通讯作者：
Hopfner, Karl-Peter
影响因子：
11.2
作者：
El-Shemerly, M;Janscak, P;Ferrari, S
通讯作者：
Ferrari, S