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The molecular basis of human transcription-coupled DNA repair

Nature Cell Biology volume 27, pages 1230–1239 (2025)Cite this article

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Abstract

The stalling of RNA polymerase II (RNAPII) on DNA lesions triggers transcription-coupled DNA repair (TCR). Although the initial assembly of the TCR complex is known, recent advances have substantially deepened our understanding of its mechanisms. The elongation factor ELOF1 and DNA-binding protein STK19 have been identified as key TCR factors, with new insights into their functions. Cryo-electron microscopy of repair intermediates and mutational analyses have elucidated how TCR proteins interact with damage-stalled RNAPII. A newly discovered transcription-coupled pathway resolves DNA–protein crosslinks using only early TCR proteins. Here we integrate these advances, outlining the TCR mechanism step by step. First we discuss how early TCR factors ubiquitylate RNAPII, then we examine the transition to later nucleotide excision repair stages, and finally, the fate of damage-stalled RNAPII. Despite these advancements, significant gaps remain in our understanding of TCR mechanisms and we discuss these along with potential future research directions.

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Fig. 1: ELOF1 stabilizes CSA on RNAPII during TCR.
Fig. 2: Initial TCR steps for a canonical NER or DPC lesion.
Fig. 3: Model of the RNAPII-bound TCR complex with STK19 and core TFIIH.
Fig. 4: Mechanistic TCR model from early to late steps.
Fig. 5: Fate of RNAPII during TCR.

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Acknowledgements

The laboratory of M.S.L. was supported by the ERC Consolidator Grant 101043815. We thank G. Kokic for insightful discussions.

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  1. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

    Paula J. van der Meer & Martijn S. Luijsterburg

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  1. Paula J. van der Meer
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P.J.v.d.M. and M.S.L. drafted the manuscript and generated all of the figures.

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Correspondence to Martijn S. Luijsterburg.

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van der Meer, P.J., Luijsterburg, M.S. The molecular basis of human transcription-coupled DNA repair. Nat Cell Biol 27, 1230–1239 (2025). https://doi.org/10.1038/s41556-025-01715-9

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