Model of ATM and ATR functions in SV40 DNA replication.

<p>(I) Tag initiates viral DNA replication at the viral origin of replication (blue) and the two replication forks progress bidirectionally (red arrowheads). For simplicity, proteins are not shown. (II) Viral DNA replicates quickly until the forks converge to form a late Cairns intermediate (III), which slowly completes replication. (IV) Topoisomerase IIα decatenates fully replicated DNA molecules, yielding two form I daughter molecules. (V) When ATM is inhibited, a one-ended double strand break at a replication fork leads to loss of the replication machinery, while the other fork continues to replicate DNA, generating a rolling circle (VI). (VII) ATM kinase activity facilitates the repair of one-ended double strand breaks. (VIII) When ATR is inhibited, a stalled replication fork remains stable until a functional replication fork approaches it, generating a broken replication intermediate (IX). (X) ATR kinase activity facilitates convergence of moving fork with the stalled fork. We suggest that in the presence of ATM and ATR, repair proteins act on the defective intermediates V and IX to reassemble an intermediate with two functional forks.