The Company of Biologists, Journal of Cell Science, 2014
DOI: 10.1242/jcs.152678
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Genetic instability, a hallmark of cancer, can occur when the replication machinery encounters a barrier. The intra-S phase checkpoint maintains stalled replication forks in a replication-competent configuration by phosphorylating replisome components and DNA repair proteins to prevent forks from catastrophically collapsing. Here we report a novel Chk1- and Cds1(Chk2)-independent function for Rad3(ATR), the core S. pombe checkpoint sensor kinase: Rad3(ATR) regulates the association of recombination factors with collapsed forks thus limiting their genetic instability. We further reveal antagonistic roles for Rad3(ATR) and the 9-1-1 clamp: Rad3(ATR) restrains MRN- and Exo1-dependent resection while the 9-1-1 complex promotes Exo1 activity. Interestingly the MRN complex, but not its nuclease activity, promotes resection and the subsequent association of recombination factors at collapsed forks. The biological significance of this regulation is revealed by the observation that Rad3(ATR) prevents Exo1-dependent genome instability upstream a collapsed fork without affecting the efficiency of recombination-mediated replication-restart. We propose the interplay between Rad3(ATR) and the 9-1-1 clamp functions to fine-tune the balance between the need for recovery of replication via recombination and the risk of increased genome instability.