Subhendu K. Das, Sharmistha Karmakar, Harish Venkatachalapathy, Rajiv Kumar Jha, Eric Batchelor, David Levens
{"title":"Excessive MYC-topoisome activity triggers acute DNA damage, MYC degradation, and replacement by a p53-topoisome","authors":"Subhendu K. Das, Sharmistha Karmakar, Harish Venkatachalapathy, Rajiv Kumar Jha, Eric Batchelor, David Levens","doi":"10.1016/j.molcel.2024.10.006","DOIUrl":null,"url":null,"abstract":"Hyperproliferation driven by the protooncogene MYC may lead to tumor suppressor p53 activating DNA damage that has been presumed to derive from hypertranscription and over-replication. Here, we report that excessive MYC-topoisome (MYC/topoisomerase 1/topoisomerase 2) activity acutely damages DNA-activating pATM and p53. In turn, MYC is shut off and degraded, releasing TOP1 and TOP2A from MYC topoisomes <em>in vitro</em> and <em>in vivo</em>. To manage the topological and torsional stress generated at its target genes, p53 assembles a separate topoisome. Because topoisomerase activity is intrinsically DNA damaging, p53 topoisomes provoke an initial burst of DNA damage. Because p53, unlike MYC, upregulates the DNA-damage response (DDR) and activates tyrosyl-DNA-phosphodiesterase (TDP) 1 and TDP2, it suppresses further topoisome-mediated damage. The physical coupling and activation of TOP1 and TOP2 by p53 creates a tool that supports p53-target expression while braking MYC-driven proliferation in mammalian cells.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":null,"pages":null},"PeriodicalIF":14.5000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.molcel.2024.10.006","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Hyperproliferation driven by the protooncogene MYC may lead to tumor suppressor p53 activating DNA damage that has been presumed to derive from hypertranscription and over-replication. Here, we report that excessive MYC-topoisome (MYC/topoisomerase 1/topoisomerase 2) activity acutely damages DNA-activating pATM and p53. In turn, MYC is shut off and degraded, releasing TOP1 and TOP2A from MYC topoisomes in vitro and in vivo. To manage the topological and torsional stress generated at its target genes, p53 assembles a separate topoisome. Because topoisomerase activity is intrinsically DNA damaging, p53 topoisomes provoke an initial burst of DNA damage. Because p53, unlike MYC, upregulates the DNA-damage response (DDR) and activates tyrosyl-DNA-phosphodiesterase (TDP) 1 and TDP2, it suppresses further topoisome-mediated damage. The physical coupling and activation of TOP1 and TOP2 by p53 creates a tool that supports p53-target expression while braking MYC-driven proliferation in mammalian cells.
期刊介绍:
Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.