The extent of error-prone replication-restart by homologous recombination is controlled by Exo1 and checkpoint proteins

Carr, Antony, Lambert, Sarah A E, Tsang, Ellen, Miyabe, Izumi, Iraqui, Ismail and Zheng, Jiping (2014) The extent of error-prone replication-restart by homologous recombination is controlled by Exo1 and checkpoint proteins. Journal of Cell Science, 127 (13). pp. 2983-2994. ISSN 0021-9533

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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 Cds1Chk2-independent function for Rad3ATR, the core S. pombe checkpoint sensor kinase: Rad3ATR regulates the association of recombination factors with collapsed forks thus limiting their genetic instability. We further reveal antagonistic roles for Rad3ATR and the 9-1-1 clamp: Rad3ATR 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 Rad3ATR prevents Exo1-dependent genome instability upstream a collapsed fork without affecting the efficiency of recombination-mediated replication-restart. We propose the interplay between Rad3ATR 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.

Item Type: Article
Keywords: checkpoint, genome instability, homologous recombination
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science
Depositing User: Jill Kirby
Date Deposited: 28 Jul 2014 11:23
Last Modified: 02 Jul 2019 19:53

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