DNA–protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair and aldehyde clearance processes cause progeria, including Ruijs–Aalfs syndrome (RJALS) and AMeD syndrome (AMeDS) in humans. Although the elimination of DPC during replication has been well established, how cells overcome DPC lesions in transcription remains elusive. Here we show that endogenous aldehyde-induced DPC roadblocks are efficiently resolved by transcription-coupled repair (TCR). We develop a high-throughput sequencing technique to measure the genome-wide distribution of DPCs (DPC-seq). Using proteomics and DPC-seq, we demonstrate that the conventional TCR complex as well as VCP/p97 and the proteasome are required for the removal of formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcription obstacles. Finally, a mouse model lacking both aldehyde clearance and TCR confirms endogenous DPC accumulation in actively transcribed regions. Collectively, our data provide evidence that transcription-coupled DPC repair (TC-DPCR) as well as aldehyde clearance are crucial for protecting against metabolic genotoxin, thus explaining the molecular pathogenesis of AMeDS and other disorders associated with defects in TCR, such as Cockayne syndrome.

醛诱导的 DNA-蛋白质交联 (DPC) 会干扰复制和转录。 DPC 修复和醛清除过程的遗传性缺陷会导致早衰症，包括人类的 Ruijs-Aalfs 综合征 (RJALS) 和 AMeD 综合征 (AMeDS)。尽管复制过程中 DPC 的消除已得到充分证实，但细胞如何克服转录中的 DPC 损伤仍然难以捉摸。在这里，我们证明内源性醛诱导的 DPC 障碍可以通过转录偶联修复 (TCR) 有效解决。我们开发了一种高通量测序技术来测量 DPC 的全基因组分布 (DPC-seq)。使用蛋白质组学和 DPC-seq，我们证明传统的 TCR 复合物以及 VCP/p97 和蛋白酶体是去除甲醛诱导的 DPC 所必需的。 RNAPII 转录物的 TFIIS 依赖性切割可防止转录障碍。最后，缺乏醛清除和 TCR 的小鼠模型证实了活跃转录区域内源性 DPC 的积累。总的来说，我们的数据提供了证据，表明转录偶联 DPC 修复 (TC-DPCR) 以及醛清除对于预防代谢性基因毒素至关重要，从而解释了 AMeDS 和与 TCR 缺陷相关的其他疾病（例如 Cockayne 综合征）的分子发病机制。