STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment
Ramadhin AR, Lee S-H, Zhou D, Testa Salmazo AP, Gonzalo-Hansen C, van Sluis M, Blom CMA, Janssens RC, Raams A, Dekkers D, Bezstarosti K, Slade D, Vermeulen W, Pines A, Demmers JAA, Bernecky C, Sixma TK, Marteijn JA. STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment. Molecular Cell.
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Author
Ramadhin, Anisha R.;
Lee, Shun-Hsiao;
Zhou, Di;
Testa Salmazo, Anita PISTA;
Gonzalo-Hansen, Camila;
van Sluis, Marjolein;
Blom, Cindy M.A.;
Janssens, Roel C.;
Raams, Anja;
Dekkers, Dick;
Bezstarosti, Karel;
Slade, Dea
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All
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Abstract
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 CRL4CSA ubiquitin ligase and UVSSA. RNA Pol II ubiquitylation at RPB1-K1268 by CRL4CSA 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 CRL4CSA 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 CRL4CSA 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.
Publishing Year
Date Published
2024-11-14
Journal Title
Molecular Cell
Publisher
Elsevier
Acknowledgement
We thank N. Thompson and R. Burgess for the 8WG16 hybridoma cell line. This research was further supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Lab Support Facility (LSF) and the Preclinical Facility (PCF). This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. Research at the Netherlands Cancer Institute is supported by institutional grants of the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sport. This study was supported by a VICI (VI.C.182.025) and a TOP Grant (714.017.003) of the Netherlands Organization for Scientific Research.
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Ramadhin AR, Lee S-H, Zhou D, et al. STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment. Molecular Cell. doi:10.1016/j.molcel.2024.10.030
Ramadhin, A. R., Lee, S.-H., Zhou, D., Testa Salmazo, A. P., Gonzalo-Hansen, C., van Sluis, M., … Marteijn, J. A. (n.d.). STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment. Molecular Cell. Elsevier. https://doi.org/10.1016/j.molcel.2024.10.030
Ramadhin, Anisha R., Shun-Hsiao Lee, Di Zhou, Anita P Testa Salmazo, Camila Gonzalo-Hansen, Marjolein van Sluis, Cindy M.A. Blom, et al. “STK19 Drives Transcription-Coupled Repair by Stimulating Repair Complex Stability, RNA Pol II Ubiquitylation, and TFIIH Recruitment.” Molecular Cell. Elsevier, n.d. https://doi.org/10.1016/j.molcel.2024.10.030.
A. R. Ramadhin et al., “STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment,” Molecular Cell. Elsevier.
Ramadhin AR, Lee S-H, Zhou D, Testa Salmazo AP, Gonzalo-Hansen C, van Sluis M, Blom CMA, Janssens RC, Raams A, Dekkers D, Bezstarosti K, Slade D, Vermeulen W, Pines A, Demmers JAA, Bernecky C, Sixma TK, Marteijn JA. STK19 drives transcription-coupled repair by stimulating repair complex stability, RNA Pol II ubiquitylation, and TFIIH recruitment. Molecular Cell.
Ramadhin, Anisha R., et al. “STK19 Drives Transcription-Coupled Repair by Stimulating Repair Complex Stability, RNA Pol II Ubiquitylation, and TFIIH Recruitment.” Molecular Cell, Elsevier, doi:10.1016/j.molcel.2024.10.030.
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