Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA polymerase II, causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions. However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR–Cas9 screen, we identified the elongation factor ELOF1 as an important factor in the transcription stress response following DNA damage. We show that ELOF1 has an evolutionarily conserved role in transcription-coupled nucleotide excision repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair transcription-blocking lesions and resume transcription. Additionally, ELOF1 modulates transcription to protect cells against transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms.

正确的转录对生命至关重要。然而，DNA 损伤严重阻碍了 RNA 聚合酶 II 的延伸，导致转录抑制和转录复制冲突。细胞配备了复杂的机制来抵消这些转录阻断损伤的严重后果。然而，确切的机制和所涉及的因素在很大程度上仍然未知。在这里，使用全基因组 CRISPR–Cas9 筛选，我们将延伸因子 ELOF1 确定为 DNA 损伤后转录应激反应的重要因素。我们表明 ELOF1 在转录偶联核苷酸切除修复 (TC-NER) 中具有进化保守作用，它促进 TC-NER 因子 UVSSA 和 TFIIH 的募集，以有效修复转录阻断损伤并恢复转录。此外，ELOF1 调节转录以保护细胞免受转录介导的复制压力，从而保持基因组稳定性。因此，ELOF1 通过两种不同的机制保护转录机制免受 DNA 损伤。