Claspin recruits Cdc7 kinase for initiation of DNA replication in human cells

Chi-Chun Yang, Masahiro Suzuki, Shiori Yamakawa, Syuzi Uno, Ai Ishii, Satoshi Yamazaki, Rino Fukatsu, Ryo Fujisawa, Kenji Sakimura, Toshiki Tsurimoto and Hisao Masai ()
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Chi-Chun Yang: Tokyo Metropolitan Institute of Medical Science
Masahiro Suzuki: Tokyo Metropolitan Institute of Medical Science
Shiori Yamakawa: Tokyo Metropolitan Institute of Medical Science
Syuzi Uno: Tokyo Metropolitan Institute of Medical Science
Ai Ishii: Tokyo Metropolitan Institute of Medical Science
Satoshi Yamazaki: Tokyo Metropolitan Institute of Medical Science
Rino Fukatsu: Tokyo Metropolitan Institute of Medical Science
Ryo Fujisawa: Faculty of Science, Kyushu University 744 Motooka, Nishi-ku
Kenji Sakimura: Brain Research Institute, Niigata University
Toshiki Tsurimoto: Faculty of Science, Kyushu University 744 Motooka, Nishi-ku
Hisao Masai: Tokyo Metropolitan Institute of Medical Science

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Claspin transmits replication stress signal from ATR to Chk1 effector kinase as a mediator. It also plays a role in efficient replication fork progression during normal growth. Here we have generated conditional knockout of Claspin and show that Claspin knockout mice are dead by E12.5 and Claspin knockout mouse embryonic fibroblast (MEF) cells show defect in S phase. Using the mutant cell lines, we report the crucial roles of the acidic patch (AP) near the C terminus of Claspin in initiation of DNA replication. Cdc7 kinase binds to AP and this binding is required for phosphorylation of Mcm. AP is involved also in intramolecular interaction with a N-terminal segment, masking the DNA-binding domain and a newly identified PIP motif, and Cdc7-mediated phosphorylation reduces the intramolecular interaction. Our results suggest a new role of Claspin in initiation of DNA replication during normal S phase through the recruitment of Cdc7 that facilitates phosphorylation of Mcm proteins.

Date: 2016
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DOI: 10.1038/ncomms12135

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