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Human CDK18 promotes replication stress signaling and genome stability

Research output: Contribution to journal › Article › peer-review

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Human CDK18 promotes replication stress signaling and genome stability. / Barone, Giancarlo; Staples, Christopher J; Ganesh, Anil et al.
In: Nucleic Acids Research, Vol. 44, No. 18, 14.10.2016, p. 8772-8785.

Research output: Contribution to journal › Article › peer-review

HarvardHarvard

Barone, G, Staples, CJ, Ganesh, A, Patterson, KW, Bryne, DP, Myers, KN, Patil, AA, Eyers, CE, Maslen, S, Skehel, JM, Eyers, PA & Collis, SJ 2016, 'Human CDK18 promotes replication stress signaling and genome stability', Nucleic Acids Research, vol. 44, no. 18, pp. 8772-8785. https://doi.org/10.1093/nar/gkw615

APA

Barone, G., Staples, C. J., Ganesh, A., Patterson, K. W., Bryne, D. P., Myers, K. N., Patil, A. A., Eyers, C. E., Maslen, S., Skehel, J. M., Eyers, P. A., & Collis, S. J. (2016). Human CDK18 promotes replication stress signaling and genome stability. Nucleic Acids Research, 44(18), 8772-8785. https://doi.org/10.1093/nar/gkw615

CBE

Barone G, Staples CJ, Ganesh A, Patterson KW, Bryne DP, Myers KN, Patil AA, Eyers CE, Maslen S, Skehel JM, et al. 2016. Human CDK18 promotes replication stress signaling and genome stability. Nucleic Acids Research. 44(18):8772-8785. https://doi.org/10.1093/nar/gkw615

MLA

Barone, Giancarlo et al. "Human CDK18 promotes replication stress signaling and genome stability". Nucleic Acids Research. 2016, 44(18). 8772-8785. https://doi.org/10.1093/nar/gkw615

VancouverVancouver

Barone G, Staples CJ, Ganesh A, Patterson KW, Bryne DP, Myers KN et al. Human CDK18 promotes replication stress signaling and genome stability. Nucleic Acids Research. 2016 Oct 14;44(18):8772-8785. Epub 2016 Jul 5. doi: 10.1093/nar/gkw615

Author

Barone, Giancarlo ; Staples, Christopher J ; Ganesh, Anil et al. / Human CDK18 promotes replication stress signaling and genome stability. In: Nucleic Acids Research. 2016 ; Vol. 44, No. 18. pp. 8772-8785.

RIS

TY - JOUR

T1 - Human CDK18 promotes replication stress signaling and genome stability

AU - Barone, Giancarlo

AU - Staples, Christopher J

AU - Ganesh, Anil

AU - Patterson, Karl W

AU - Bryne, Dominic P

AU - Myers, Katie N

AU - Patil, Abhijit A

AU - Eyers, Claire E

AU - Maslen, Sarah

AU - Skehel, J Mark

AU - Eyers, Patrick A

AU - Collis, Spencer J

N1 - © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

PY - 2016/10/14

Y1 - 2016/10/14

N2 - Cyclin-dependent kinases (CDKs) coordinate cell cycle checkpoints with DNA repair mechanisms that together maintain genome stability. However, the myriad mechanisms that can give rise to genome instability are still to be fully elucidated. Here, we identify CDK18 (PCTAIRE 3) as a novel regulator of genome stability, and show that depletion of CDK18 causes an increase in endogenous DNA damage and chromosomal abnormalities. CDK18-depleted cells accumulate in early S-phase, exhibiting retarded replication fork kinetics and reduced ATR kinase signaling in response to replication stress. Mechanistically, CDK18 interacts with RAD9, RAD17 and TOPBP1, and CDK18-deficiency results in a decrease in both RAD17 and RAD9 chromatin retention in response to replication stress. Importantly, we demonstrate that these phenotypes are rescued by exogenous CDK18 in a kinase-dependent manner. Collectively, these data reveal a rate-limiting role for CDK18 in replication stress signalling and establish it as a novel regulator of genome integrity.

AB - Cyclin-dependent kinases (CDKs) coordinate cell cycle checkpoints with DNA repair mechanisms that together maintain genome stability. However, the myriad mechanisms that can give rise to genome instability are still to be fully elucidated. Here, we identify CDK18 (PCTAIRE 3) as a novel regulator of genome stability, and show that depletion of CDK18 causes an increase in endogenous DNA damage and chromosomal abnormalities. CDK18-depleted cells accumulate in early S-phase, exhibiting retarded replication fork kinetics and reduced ATR kinase signaling in response to replication stress. Mechanistically, CDK18 interacts with RAD9, RAD17 and TOPBP1, and CDK18-deficiency results in a decrease in both RAD17 and RAD9 chromatin retention in response to replication stress. Importantly, we demonstrate that these phenotypes are rescued by exogenous CDK18 in a kinase-dependent manner. Collectively, these data reveal a rate-limiting role for CDK18 in replication stress signalling and establish it as a novel regulator of genome integrity.

U2 - 10.1093/nar/gkw615

DO - 10.1093/nar/gkw615

M3 - Article

C2 - 27382066

VL - 44

SP - 8772

EP - 8785

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 18

ER -