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

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Cyclin A/CDK2 mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication. / Copeland, Nikki; Sercombe, Heather E; Wilson, Rosemary H. C. et al.
In: Journal of Cell Science, Vol. 128, No. 8, 15.04.2015, p. 1518-1527.

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Harvard

Copeland, N, Sercombe, HE, Wilson, RHC & Coverley, D 2015, 'Cyclin A/CDK2 mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication', Journal of Cell Science, vol. 128, no. 8, pp. 1518-1527. https://doi.org/10.1242/jcs.161919

APA

Vancouver

Copeland N, Sercombe HE, Wilson RHC, Coverley D. Cyclin A/CDK2 mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication. Journal of Cell Science. 2015 Apr 15;128(8):1518-1527. Epub 2015 Mar 3. doi: 10.1242/jcs.161919

Author

Copeland, Nikki ; Sercombe, Heather E ; Wilson, Rosemary H. C. et al. / Cyclin A/CDK2 mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication. In: Journal of Cell Science. 2015 ; Vol. 128, No. 8. pp. 1518-1527.

Bibtex

@article{31abbb968a6e43fcba9d924cddb6c6eb,
title = "Cyclin A/CDK2 mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication",
abstract = "CIZ1 is a nuclear matrix protein that cooperates with cyclin A/CDK2 to promote mammalian DNA replication. We show here that cyclin A/CDK2 also negatively regulates CIZ1 activity via 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 nuclear matrix binding capability, and interaction with CDC6 is not affected. Phospho-threonine 192-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. 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 itself phosphorylated.",
keywords = "CDK, replisome, DNA replication, cell cycle, cancer",
author = "Nikki Copeland and Sercombe, {Heather E} and Wilson, {Rosemary H. C.} and Dawn Coverley",
year = "2015",
month = apr,
day = "15",
doi = "10.1242/jcs.161919",
language = "English",
volume = "128",
pages = "1518--1527",
journal = "Journal of Cell Science",
issn = "0021-9533",
publisher = "Company of Biologists Ltd",
number = "8",

}

RIS

TY - JOUR

T1 - Cyclin A/CDK2 mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication

AU - Copeland, Nikki

AU - Sercombe, Heather E

AU - Wilson, Rosemary H. C.

AU - Coverley, Dawn

PY - 2015/4/15

Y1 - 2015/4/15

N2 - CIZ1 is a nuclear matrix protein that cooperates with cyclin A/CDK2 to promote mammalian DNA replication. We show here that cyclin A/CDK2 also negatively regulates CIZ1 activity via 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 nuclear matrix binding capability, and interaction with CDC6 is not affected. Phospho-threonine 192-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. 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 itself phosphorylated.

AB - CIZ1 is a nuclear matrix protein that cooperates with cyclin A/CDK2 to promote mammalian DNA replication. We show here that cyclin A/CDK2 also negatively regulates CIZ1 activity via 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 nuclear matrix binding capability, and interaction with CDC6 is not affected. Phospho-threonine 192-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. 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 itself phosphorylated.

KW - CDK

KW - replisome

KW - DNA replication

KW - cell cycle

KW - cancer

U2 - 10.1242/jcs.161919

DO - 10.1242/jcs.161919

M3 - Journal article

VL - 128

SP - 1518

EP - 1527

JO - Journal of Cell Science

JF - Journal of Cell Science

SN - 0021-9533

IS - 8

ER -