title: The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks.
abstract: DNA lesions interfere with DNA and RNA polymerase activity. Cyclobutane pyrimidine dimers and photoproducts generated by ultraviolet irradiation cause stalling of RNA polymerase II, activation of transcription-coupled repair enzymes, and inhibition of RNA synthesis. During the S phase of the cell cycle, collision of replication forks with damaged DNA blocks ongoing DNA replication while also triggering a biochemical signal that suppresses the firing of distant origins of replication. Whether the transcription machinery is affected by the presence of DNA double-strand breaks remains a long-standing question. Here we monitor RNA polymerase I (Pol I) activity in mouse cells exposed to genotoxic stress and show that induction of DNA breaks leads to a transient repression in Pol I transcription. Surprisingly, we find Pol I inhibition is not itself the direct result of DNA damage but is mediated by ATM kinase activity and the repair factor proteins NBS1 (also known as NLRP2) and MDC1. Using live-cell imaging, laser micro-irradiation, and photobleaching technology we demonstrate that DNA lesions interfere with Pol I initiation complex assembly and lead to a premature displacement of elongating holoenzymes from ribosomal DNA. Our data reveal a novel ATM/NBS1/MDC1-dependent pathway that shuts down ribosomal gene transcription in response to chromosome breaks.
authors.affiliation: Experimental Immunology, NCI.
authors.forename: Michael
authors.initials: M
authors.lastname: Kruhlak
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Crouch
authors.forename: Marika
authors.initials: M
authors.lastname: Orlov
authors.forename: Carolina
authors.initials: C
authors.lastname: Montaño
authors.forename: Stanislaw A
authors.initials: SA
authors.lastname: Gorski
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
authors.forename: Robert D
authors.initials: RD
authors.lastname: Phair
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002466:Cell Nucleolus / Q000235:genetics / Q000473:pathology; D019457:Chromosome Breakage; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004275:DNA, Ribosomal; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C508937:MDC1 protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D012318:RNA Polymerase I