ArticleNucleic acids research2010
Deregulated Cdc6 inhibits DNA replication and suppresses Cdc7-mediated phosphorylation of Mcm2-7 complex.
Article in Nucleic acids research, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Characterization of an archaeal virus-host system reveals massive genomic rearrangements in a laboratory strain.Frontiers in microbiology · 2023Article
- Reconstruction of pathway modification induced by nicotinamide using multi-omic network analyses in triple negative breast cancer.Scientific reports · 2017Article
- Molecular pathology of cutaneous melanoma.Melanoma management · 2014Review
- Dbf4: the whole is greater than the sum of its parts.Cell cycle (Georgetown, Tex.) · 2013Review
- A nontranscriptional role for HIF-1α as a direct inhibitor of DNA replication.Science signaling · 2013Article
- Biphasic chromatin binding of histone chaperone FACT during eukaryotic chromatin DNA replication.Biochimica et biophysica acta · 2011Article
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mcm2-7 is recruited to eukaryotic origins of DNA replication by origin recognition complex, Cdc6 and Cdt1 thereby licensing the origins. Cdc6 is essential for origin licensing during DNA replication and is readily destabilized from chromatin after Mcm2-7 loading. Here, we show that after origin licensing, deregulation of Cdc6 suppresses DNA replication in Xenopus egg extracts without the involvement of ATM/ATR-dependent checkpoint pathways. DNA replication is arrested specifically after chromatin binding of Cdc7, but before Cdk2-dependent pathways and deregulating Cdc6 after this step does not impair activation of origin firing or elongation. Detailed analyses revealed that Cdc6 deregulation leads to strong suppression of Cdc7-mediated hyperphosphorylation of Mcm4 and subsequent chromatin loading of Cdc45, Sld5 and DNA polymerase α. Mcm2 phosphorylation is also repressed although to a lesser extent. Remarkably, Cdc6 itself does not directly inhibit Cdc7 kinase activity towards Mcm2-4-6-7 in purified systems, rather modulates Mcm2-7 phosphorylation on chromatin context. Taken together, we propose that Cdc6 on chromatin acts as a modulator of Cdc7-mediated phosphorylation of Mcm2-7, and thus destabilization of Cdc6 from chromatin after licensing is a key event ensuring proper transition to the initiation of DNA replication.
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