Flap endonuclease 1 repairs DNA-protein cross-links via ADP-ribosylation–dependent mechanisms

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-01-10 DOI:10.1126/sciadv.ads2919

Yilun Sun, Lisa M. Jenkins, Lara H. El Touny, Linying Zhu, Xi Yang, Ukhyun Jo, Lauren Escobedo, Tapan K. Maity, Liton Kumar Saha, Isabel Uribe, Sourav Saha, Shunichi Takeda, Anthony K. L. Leung, Ken Cheng, Yves Pommier

{"title":"Flap endonuclease 1 repairs DNA-protein cross-links via ADP-ribosylation–dependent mechanisms","authors":"Yilun Sun, Lisa M. Jenkins, Lara H. El Touny, Linying Zhu, Xi Yang, Ukhyun Jo, Lauren Escobedo, Tapan K. Maity, Liton Kumar Saha, Isabel Uribe, Sourav Saha, Shunichi Takeda, Anthony K. L. Leung, Ken Cheng, Yves Pommier","doi":"10.1126/sciadv.ads2919","DOIUrl":null,"url":null,"abstract":"DNA-protein cross-links (DPCs) are among the most detrimental genomic lesions. They are ubiquitously produced by formaldehyde (FA), and failure to repair FA-induced DPCs blocks chromatin-based processes, leading to neurodegeneration and cancer. The type, structure, and repair of FA-induced DPCs remain largely unknown. Here, we profiled the proteome of FA-induced DPCs and found that flap endonuclease 1 (FEN1) resolves FA-induced DPCs. We revealed that FA also damages DNA bases adjoining the DPCs, leading to DPC-conjugated 5′ flap structures via the base excision repair (BER) pathway. We also found that FEN1 repairs enzymatic topoisomerase II (TOP2)–DPCs. Furthermore, we report that both FA-induced and TOP2-DPCs are adenosine diphosphate (ADP) ribosylated by poly(ADP-ribose) polymerase 1 (PARP1). PARylation of the DPCs in association with FEN1 PARylation at residue E285 is required for the recruitment of FEN1. Our work unveils the identity of proteins forming FA-induced DPCs and a previously unrecognized PARP1-FEN1 nuclease pathway repairing both FA- and TOP2-DPCs.","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"35 1","pages":""},"PeriodicalIF":11.7000,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1126/sciadv.ads2919","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

DNA-protein cross-links (DPCs) are among the most detrimental genomic lesions. They are ubiquitously produced by formaldehyde (FA), and failure to repair FA-induced DPCs blocks chromatin-based processes, leading to neurodegeneration and cancer. The type, structure, and repair of FA-induced DPCs remain largely unknown. Here, we profiled the proteome of FA-induced DPCs and found that flap endonuclease 1 (FEN1) resolves FA-induced DPCs. We revealed that FA also damages DNA bases adjoining the DPCs, leading to DPC-conjugated 5′ flap structures via the base excision repair (BER) pathway. We also found that FEN1 repairs enzymatic topoisomerase II (TOP2)–DPCs. Furthermore, we report that both FA-induced and TOP2-DPCs are adenosine diphosphate (ADP) ribosylated by poly(ADP-ribose) polymerase 1 (PARP1). PARylation of the DPCs in association with FEN1 PARylation at residue E285 is required for the recruitment of FEN1. Our work unveils the identity of proteins forming FA-induced DPCs and a previously unrecognized PARP1-FEN1 nuclease pathway repairing both FA- and TOP2-DPCs.

查看原文本刊更多论文

皮瓣内切酶1通过adp -核糖基化依赖机制修复dna -蛋白交联

dna -蛋白质交联（DPCs）是最有害的基因组病变之一。它们是由甲醛（FA）普遍产生的，而FA诱导的DPCs修复失败会阻断基于染色质的过程，导致神经变性和癌症。fa诱导的DPCs的类型、结构和修复在很大程度上仍然未知。在这里，我们分析了fa诱导的DPCs的蛋白质组，发现皮瓣内切酶1 （FEN1）可以分解fa诱导的DPCs。我们发现FA也会破坏dpc附近的DNA碱基，通过碱基切除修复（BER）途径导致dpc共轭的5 '瓣结构。我们还发现FEN1可以修复酶拓扑异构酶II (TOP2) -DPCs。此外，我们报道fa诱导的和TOP2-DPCs都是被聚（ADP-核糖）聚合酶1 （PARP1）核糖化的二磷酸腺苷（ADP）。DPCs与FEN1在E285位点的聚合对于FEN1的募集是必需的。我们的工作揭示了形成FA诱导的DPCs的蛋白质的身份，以及先前未被识别的PARP1-FEN1核酸酶途径修复FA-和TOP2-DPCs。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.