Cyclin-A-CDK2-mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication

Journal of Cell Science
Nikki CopelandDawn Coverley

Abstract

CIZ1 is a nuclear matrix protein that cooperates with cyclin A2 (encoded by CCNA2) and CDK2 to promote mammalian DNA replication. We show here that cyclin-A-CDK2 also negatively regulates CIZ1 activity by phosphorylation at threonines 144, 192 and 293. Phosphomimetic mutants do not promote DNA replication in cell-free and cell-based assays, and also have a dominant-negative effect on replisome formation at the level of PCNA recruitment. Phosphorylation blocks direct interaction with cyclin-A-CDK2 and recruitment of endogenous cyclin A to the nuclear matrix. In contrast, phosphomimetic CIZ1 retains the ability to bind to the nuclear matrix, and its interaction with CDC6 is not affected. Phospho-T192-specific antibodies confirm that CIZ1 is phosphorylated during S phase and G2, and show that phosphorylation at this site occurs at post-initiation concentrations of cyclin-A-CDK2. Taken together, the data suggest that CIZ1 is a kinase sensor that promotes initiation of DNA replication at low kinase levels, when in a hypophosphorylated state that is permissive for cyclin-A-CDK2 interaction and delivery to licensed origins, but blocks delivery at higher kinase levels when it is phosphorylated.

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Citations

Feb 11, 2016·International Journal of Molecular Sciences·Qiang LiuJu Liu
Feb 26, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Liu LeiShaochuang Wang
May 11, 2016·Experimental Neurology·Jianfeng XiaoMark S LeDoux
Dec 31, 2016·Biomolecules·Tekle PauzaiteNikki A Copeland
Aug 12, 2018·FEBS Letters·Jianfeng XiaoMark S LeDoux
Jun 13, 2020·Journal of Cellular Physiology·Zhecun WangShenming Wang
Sep 20, 2017·Proceedings of the National Academy of Sciences of the United States of America·Hongjae SunwooJeannie T Lee
Oct 24, 2020·Scientific Reports·Urvi ThackerNikki A Copeland

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