Human CDK18 promotes replication stress signaling and genome stability


Barone, G, Staples, C, Ganesh, A, Patterson, K, Byrne, D, Myers, K, Patil, A, Eyers, CE ORCID: 0000-0002-3223-5926, Maslen, S, Skehel, M et al (show 2 more authors) (2016) Human CDK18 promotes replication stress signaling and genome stability. Nucleic Acids Research, 44 (18). pp. 8772-8785.

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: Cell Line, Tumor, Chromatin, Humans, DNA Damage, Chromosome Aberrations, Genomic Instability, Cyclin-Dependent Kinases, Cell Cycle Proteins, RNA, Small Interfering, Signal Transduction, DNA Replication, RNA Interference, Protein Binding, Phosphorylation, Protein Interaction Domains and Motifs, Stress, Physiological, Cell Cycle Checkpoints
Depositing User: Symplectic Admin
Date Deposited: 13 Jul 2016 10:49
Last Modified: 19 Jan 2023 07:34
DOI: 10.1093/nar/gkw615
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3002281
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