日本名古屋大学Tomoo Ogi和Mayuko Shimada研究组在研究中取得进展。他们探明了内源性醛诱导的DNA -蛋白交联通过转录偶联修复来解决。相关论文于2024年4月10日发表于国际顶尖学术期刊《自然—细胞生物学》杂志上。

据悉，醛类诱导的DNA-蛋白交联(DPCs)干扰了DNA的复制和转录。DNA-蛋白交联修复和醛清除过程中的遗传性缺陷，会导致早衰症、包括人类Ruijs–Aalfs综合征(RJALS)和AMeD综合征(AMeDS)。虽然在复制过程中消除DNA-蛋白交联已经很好地建立，但细胞如何克服转录中的DNA-蛋白交联损伤仍然是未知的。

本研究表明，内源性醛诱导的DNA-蛋白交联障碍可通过转录偶联修复(TCR)有效解决。研究团队开发了一种高通量测序技术来测量DNA-蛋白交联的全基因组分布(DPC-seq)。利用蛋白质组学和DPC-seq，该课题组人员证明了传统的TCR复合物以及VCP/p97和蛋白酶体，是去除甲醛诱导的DNA-蛋白交联所必需的。依赖于TFIIS的RNAPII转录物的切割可以防止转录障碍。

最后，缺乏醛清除和TCR的小鼠模型证实内源性DNA-蛋白交联在活跃转录区域积累。总的来说，他们的数据提供了证据，证明转录偶联DNA-蛋白交联修复(TC-DPCR)以及醛清除对于防止代谢性基因毒素至关重要，它们解释了AMeDS和其他与TCR缺陷相关的疾病(如Cockayne综合征)的分子发病机制。

附：英文原文

Title: Endogenous aldehyde-induced DNA–protein crosslinks are resolved by transcription-coupled repair

Author: Oka, Yasuyoshi, Nakazawa, Yuka, Shimada, Mayuko, Ogi, Tomoo

Issue&Volume: 2024-04-10

Abstract: 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.

DOI: 10.1038/s41556-024-01401-2

Source: https://www.nature.com/articles/s41556-024-01401-2