Chk1 promotes replication fork progression by controlling replication initiation
2010 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 37, 16090-16095 p.Article in journal (Refereed) Published
DNA replication starts at initiation sites termed replication origins. Metazoan cells contain many more potential origins than are activated (fired) during each S phase. Origin activation is controlled by the ATR checkpoint kinase and its downstream effector kinase Chk1, which suppresses origin firing in response to replication blocks and during normal S phase by inhibiting the cyclin-dependent kinase Cdk2. In addition to increased origin activation, cells deficient in Chk1 activity display reduced rates of replication fork progression. Here we investigate the causal relationship between increased origin firing and reduced replication fork progression. We use the Cdk inhibitor roscovitine or RNAi depletion of Cdc7 to inhibit origin firing in Chk1-inhibited or RNAi-depleted cells. We report that Cdk inhibition and depletion of Cdc7 can alleviate the slow replication fork speeds in Chk1-deficient cells. Our data suggest that increased replication initiation leads to slow replication fork progression and that Chk1 promotes replication fork progression during normal S phase by controlling replication origin activity.
Place, publisher, year, edition, pages
2010. Vol. 107, no 37, 16090-16095 p.
Cdc7, Cdk2, roscovitine, S phase checkpoint
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:su:diva-49429DOI: 10.1073/pnas.1005031107ISI: 000281799000023OAI: oai:DiVA.org:su-49429DiVA: diva2:379413
authorCount :32010-12-172010-12-142010-12-17Bibliographically approved