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

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posted on 2023-06-08, 17:56 authored by Antony CarrAntony Carr, Sarah A E Lambert, Ellen Tsang, Izumi Miyabe, Ismail Iraqui, Jiping Zheng
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.

Funding

G1100074; MRC

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Cell Science

ISSN

0021-9533

Publisher

Company of Biologists

Issue

13

Volume

127

Page range

2983-2994

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2014-07-28

First Open Access (FOA) Date

2014-07-28

First Compliant Deposit (FCD) Date

2014-07-28

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