The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks

Item Type:	Article
Title:	The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks
Creators Name:	Kruhlak, M. and Crouch, E.E. and Orlov, M. and Montaño, C. and Gorski, S.A. and Nussenzweig, A. and Misteli, T. and Phair, R.D. and Casellas, R.
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.
Keywords:	Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Line, Cell Nucleolus, Chromosome Breakage, DNA-Binding Proteins, DNA Repair, Double-Stranded DNA Breaks, Fibroblasts, Genetic Transcription, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Protein Serine-Threonine Kinases, Ribosomal RNA, Ribosomal DNA, RNA Polymerase I, Tumor Suppressor Proteins, Signal Transducing Adaptor Proteins, Animals, Mice
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	447
Number:	7145
Page Range:	730-734
Date:	7 June 2007
Official Publication:	https://doi.org/10.1038/nature05842
PubMed:	View item in PubMed

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