The molecular basis of human transcription-coupled DNA repair

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.