Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 35, Issue 12, Pages 2131-2143Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01357-14
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Funding
- NIH [RO1GM083985, R01GM104097]
- American Cancer Society [RSG-05-113-01-CCG, 120222-RSG-11-048-01-DMC]
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The DNA replication checkpoint (DRC) monitors and responds to stalled replication forks to prevent genomic instability. How core replication factors integrate into this phosphorylation cascade is incompletely understood. Here, through analysis of a unique mcm allele targeting a specific ATPase active site (mcm2DENQ), we show that the Mcm2-7 replicative helicase has a novel DRC function as part of the signal transduction cascade. This allele exhibits normal downstream mediator (Mrc1) phosphorylation, implying DRC sensor kinase activation. However, the mutant also exhibits defective effector kinase (Rad53) activation and classic DRC phenotypes. Our previous in vitro analysis showed that the mcm2DENQ mutation prevents a specific conformational change in the Mcm2-7 hexamer. We infer that this conformational change is required for its DRC role and propose that it allosterically facilitates Rad53 activation to ensure a replication-specific checkpoint response.
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