荷兰莱顿大学Martijn S. Luijsterburg等研究人员合作发现，STK19促进转录耦合DNA修复过程中受损RNAPII的清除。这一研究成果于2024年11月14日在线发表在国际学术期刊《细胞》上。
研究人员表示，转录偶联DNA修复（TCR）去除阻碍RNA聚合酶II（RNAPII）转录的大型DNA损伤。近期研究已阐明了TCR因子CSB、CSA、UVSSA和转录因子IIH（TFIIH）在损伤停滞的RNAPII周围的逐步组装。然而，过渡到下游修复步骤所需的机制和因子，包括去除RNAPII以使修复蛋白能够接触DNA损伤，仍不清楚。
研究人员鉴定了STK19作为一个TCR因子，促进这一过渡。缺失STK19并不影响初步的TCR复合物组装或RNAPII的泛素化，但会延迟损伤停滞的RNAPII清除，从而干扰下游修复反应。冷冻电镜（cryo-EM）和突变分析揭示STK19与TCR复合物结合，定位于RNAPII、UVSSA和CSA之间。结构洞察和分子建模表明，STK19将TFIIH的ATP酶亚基定位到RNAPII前方的DNA上。综上所述，这些发现为TCR所需的因子和机制提供了新的见解。
附：英文原文
Title: STK19 facilitates the clearance of lesion-stalled RNAPII during transcription-coupled DNA repair
Author: 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 Kirdk, Mats Ljungman, Rob M.F. Wolthuis, Patrick Cramer, Orlando D. Schrer, Goran Kokic, Jesper Q. Svejstrup, Martijn S. Luijsterburg
Issue&Volume: 2024-11-14
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.
DOI: 10.1016/j.cell.2024.10.018
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01200-5