Mcm2-7 Is an Active Player in the DNA Replication Checkpoint Signaling Cascade via Proposed Modulation of Its DNA Gate.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Tsai, F-L; Vijayraghavan, S; Prinz, J; MacAlpine, HK; MacAlpine, DM; Schwacha, A

Published Date

  • June 2015

Published In

Volume / Issue

  • 35 / 12

Start / End Page

  • 2131 - 2143

PubMed ID

  • 25870112

Pubmed Central ID

  • 25870112

Electronic International Standard Serial Number (EISSN)

  • 1098-5549

International Standard Serial Number (ISSN)

  • 0270-7306

Digital Object Identifier (DOI)

  • 10.1128/MCB.01357-14

Language

  • eng