ATM and ATR Activities Maintain Replication Fork Integrity during SV40 Chromatin Replication |
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Authors: | Gregory A. Sowd Nancy Yan Li Ellen Fanning |
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Affiliation: | Department of Biological Sciences, Vanderbilt University, Vanderbilt Ingram Comprehensive Cancer Center, Nashville, Tennessee, United States of America;University of Michigan, United States of America |
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Abstract: | Mutation of DNA damage checkpoint signaling kinases ataxia telangiectasia-mutated (ATM) or ATM- and Rad3-related (ATR) results in genomic instability disorders. However, it is not well understood how the instability observed in these syndromes relates to DNA replication/repair defects and failed checkpoint control of cell cycling. As a simple model to address this question, we have studied SV40 chromatin replication in infected cells in the presence of inhibitors of ATM and ATR activities. Two-dimensional gel electrophoresis and southern blotting of SV40 chromatin replication products reveal that ATM activity prevents accumulation of unidirectional replication products, implying that ATM promotes repair of replication-associated double strand breaks. ATR activity alleviates breakage of a functional fork as it converges with a stalled fork. The results suggest that during SV40 chromatin replication, endogenous replication stress activates ATM and ATR signaling, orchestrating the assembly of genome maintenance machinery on viral replication intermediates. |
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