Transcription-coupled nucleotide excision repair (TC-NER) efficiently eliminates DNA damage that impedes gene transcription by RNA polymerase II (RNA Pol II). TC-NER is initiated by the recognition of lesion-stalled RNA Pol II by CSB, which recruits the CRL4^CSA ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at RPB1-K1268 by CRL4^CSA serves as a critical TC-NER checkpoint, governing RNA Pol II stability and initiating DNA damage excision by TFIIH recruitment. However, the precise regulatory mechanisms of CRL4^CSA activity and TFIIH recruitment remain elusive. Here, we reveal human serine/threonine-protein kinase 19 (STK19) as a TC-NER factor, which is essential for correct DNA damage removal and subsequent transcription restart. Cryogenic electron microscopy (cryo-EM) studies demonstrate that STK19 is an integral part of the RNA Pol II-TC-NER complex, bridging CSA, UVSSA, RNA Pol II, and downstream DNA. STK19 stimulates TC-NER complex stability and CRL4^CSA activity, resulting in efficient RNA Pol II ubiquitylation and correct UVSSA and TFIIH binding. These findings underscore the crucial role of STK19 as a core TC-NER component.

中文翻译：

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STK19 通过刺激修复复合物稳定性、RNA Pol II 泛素化和 TFIIH 募集来驱动转录偶联修复


转录偶联核苷酸切除修复 （TC-NER） 可有效消除阻碍 RNA 聚合酶 II （RNA Pol II） 基因转录的 DNA 损伤。TC-NER 是由 CSB 识别损伤停滞的 RNA Pol II 引发的，CSB 募集 CRL4^CSA 泛素连接酶和 UVSSA。CRL4^CSA 在 RPB1-K1268 位点的 RNA Pol II 泛素化是一个关键的 TC-NER 检查点，控制 RNA Pol II 稳定性并通过 TFIIH 募集启动 DNA 损伤切除。然而，CRL4^CSA 活性和 TFIIH 募集的确切调节机制仍然难以捉摸。在这里，我们揭示了人丝氨酸/苏氨酸蛋白激酶 19 （STK19） 作为 TC-NER 因子，这对于正确去除 DNA 损伤和随后的转录重新开始至关重要。低温电子显微镜 （cryo-EM） 研究表明，STK19 是 NA POL II-TC-NER 复合物的组成部分，桥接 CSA、UVSSA、RNA Pol II 和下游 DNA。STK19 刺激 TC-NER 复合物稳定性和 CRL4^CSA 活性，导致有效的 RNA Pol II 泛素化和正确的 UVSSA 和 TFIIH 结合。这些发现强调了 STK19 作为核心 TC-NER 成分的关键作用。