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Senataxin RNA/DNA 解旋酶通过促进共转录 R 环处的复制重启动来防止 MUS81 依赖性叉降解。

Senataxin RNA/DNA helicase promotes replication restart at co-transcriptional R-loops to prevent MUS81-dependent fork degradation.

机构信息

Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.

Institute of Molecular Genetics of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic.

出版信息

Nucleic Acids Res. 2024 Sep 23;52(17):10355-10369. doi: 10.1093/nar/gkae673.

DOI:10.1093/nar/gkae673
PMID:39119900
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11417401/
Abstract

Replication forks stalled at co-transcriptional R-loops can be restarted by a mechanism involving fork cleavage-religation cycles mediated by MUS81 endonuclease and DNA ligase IV (LIG4), which presumably relieve the topological barrier generated by the transcription-replication conflict (TRC) and facilitate ELL-dependent reactivation of transcription. Here, we report that the restart of R-loop-stalled replication forks via the MUS81-LIG4-ELL pathway requires senataxin (SETX), a helicase that can unwind RNA:DNA hybrids. We found that SETX promotes replication fork progression by preventing R-loop accumulation during S-phase. Interestingly, loss of SETX helicase activity leads to nascent DNA degradation upon induction of R-loop-mediated fork stalling by hydroxyurea. This fork degradation phenotype is independent of replication fork reversal and results from DNA2-mediated resection of MUS81-cleaved replication forks that accumulate due to defective replication restart. Finally, we demonstrate that SETX acts in a common pathway with the DEAD-box helicase DDX17 to suppress R-loop-mediated replication stress in human cells. A possible cooperation between these RNA/DNA helicases in R-loop unwinding at TRC sites is discussed.

摘要

在共转录 R 环处停滞的复制叉可以通过一种机制重新启动，该机制涉及由 MUS81 内切核酸酶和 DNA 连接酶 IV（LIG4）介导的叉切割-连接循环，这可能缓解转录-复制冲突（TRC）产生的拓扑障碍，并促进 ELL 依赖性转录的重新激活。在这里，我们报告说，通过 MUS81-LIG4-ELL 途径重新启动 R 环停滞的复制叉需要解旋酶（SETX），它可以解开 RNA:DNA 杂交体。我们发现 SETX 通过在 S 期防止 R 环积累来促进复制叉的进展。有趣的是，当通过羟基脲诱导 R 环介导的叉停滞时，丧失 SETX 解旋酶活性会导致新生 DNA 降解。这种叉降解表型不依赖于复制叉反转，并且是由于 DNA2 介导的由于复制重新启动缺陷而积累的 MUS81 切割复制叉的切除引起的。最后，我们证明 SETX 在与人细胞中 R 环介导的复制应激的共同途径中与 DEAD 盒解旋酶 DDX17 作用。讨论了这些 RNA/DNA 解旋酶在 TRC 位点处 R 环解旋中的可能合作。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/d4582fa5d754/gkae673fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/ad17961e774f/gkae673figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/eb87a6367f29/gkae673fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/3dcebfeaba6a/gkae673fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/7c9c93f25fe4/gkae673fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/03def211b896/gkae673fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/261b7a333db7/gkae673fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/3f34b37d2281/gkae673fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/143c2f7db0a5/gkae673fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/d4582fa5d754/gkae673fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/ad17961e774f/gkae673figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/eb87a6367f29/gkae673fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/3dcebfeaba6a/gkae673fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/7c9c93f25fe4/gkae673fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/03def211b896/gkae673fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/261b7a333db7/gkae673fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/3f34b37d2281/gkae673fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/143c2f7db0a5/gkae673fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0497/11417401/d4582fa5d754/gkae673fig8.jpg

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