ATM and ATR Activities Maintain Replication Fork Integrity during SV40 Chromatin Replication

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. © 2013 sowd et al.