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XB-ART-41603
Nucleic Acids Res 2010 Sep 01;3816:5409-18. doi: 10.1093/nar/gkq262.
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Deregulated Cdc6 inhibits DNA replication and suppresses Cdc7-mediated phosphorylation of Mcm2-7 complex.

Kundu LR , Kumata Y , Kakusho N , Watanabe S , Furukohri A , Waga S , Seki M , Masai H , Enomoto T , Tada S .


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.

PubMed ID: 20421204
PMC ID: PMC2938227
Article link: Nucleic Acids Res


Species referenced: Xenopus laevis
Genes referenced: antxr1 atm atr cdc45 cdc6 cdc7 cdk2 cdkn1a cdt1 chek1 gins4 gmnn mcm2 mcm4 nsg1


Article Images: [+] show captions
References [+] :
Arias, Strength in numbers: preventing rereplication via multiple mechanisms in eukaryotic cells. 2007, Pubmed