STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair

IF 5.7 1区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Chemical Theory and Computation Pub Date : 2024-11-14 DOI:10.1016/j.cell.2024.10.018

Diana van den Heuvel, Marta Rodríguez-Martínez, Paula J. van der Meer, Nicolas Nieto Moreno, Jiyoung Park, Hyun-Suk Kim, Janne J.M. van Schie, Annelotte P. Wondergem, Areetha D’Souza, George Yakoub, Anna E. Herlihy, Krushanka Kashyap, Thierry Boissière, Jane Walker, Richard Mitter, Katja Apelt, Klaas de Lint, Idil Kirdök, Mats Ljungman, Rob M.F. Wolthuis, Martijn S. Luijsterburg

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引用次数: 0

Abstract

Transcription-coupled DNA repair (TCR) removes bulky DNA lesions impeding RNA polymerase II (RNAPII) transcription. Recent studies have outlined the stepwise assembly of TCR factors CSB, CSA, UVSSA, and transcription factor IIH (TFIIH) around lesion-stalled RNAPII. However, the mechanism and factors required for the transition to downstream repair steps, including RNAPII removal to provide repair proteins access to the DNA lesion, remain unclear. Here, we identify STK19 as a TCR factor facilitating this transition. Loss of STK19 does not impact initial TCR complex assembly or RNAPII ubiquitylation but delays lesion-stalled RNAPII clearance, thereby interfering with the downstream repair reaction. Cryoelectron microscopy (cryo-EM) and mutational analysis reveal that STK19 associates with the TCR complex, positioning itself between RNAPII, UVSSA, and CSA. The structural insights and molecular modeling suggest that STK19 positions the ATPase subunits of TFIIH onto DNA in front of RNAPII. Together, these findings provide new insights into the factors and mechanisms required for TCR.

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STK19 在转录耦合 DNA 修复过程中促进清除病变停滞的 RNAPII

转录耦合 DNA 修复（TCR）可清除阻碍 RNA 聚合酶 II（RNAPII）转录的大块 DNA 病变。最近的研究概述了 TCR 因子 CSB、CSA、UVSSA 和转录因子 IIH（TFIIH）围绕病变停滞的 RNAPII 逐步组装的过程。然而，过渡到下游修复步骤（包括移除 RNAPII 以提供修复蛋白进入 DNA 病变）所需的机制和因子仍不清楚。在这里，我们发现 STK19 是促进这一过渡的 TCR 因子。STK19 的缺失不会影响最初的 TCR 复合物组装或 RNAPII 泛素化，但会延迟病变停滞的 RNAPII 清除，从而干扰下游修复反应。低温电子显微镜（cryo-EM）和突变分析表明，STK19 与 TCR 复合物结合，位于 RNAPII、UVSSA 和 CSA 之间。结构洞察和分子建模表明，STK19 将 TFIIH 的 ATPase 亚基定位在 RNAPII 前面的 DNA 上。这些发现共同为 TCR 所需的因素和机制提供了新的见解。

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来源期刊

Journal of Chemical Theory and Computation 化学-物理：原子、分子和化学物理

CiteScore

9.90

自引率

16.40%

发文量

568

审稿时长

1 months

期刊介绍： The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.