2. Academic Validation
  3. Human CDK18 promotes replication stress signaling and genome stability

Human CDK18 promotes replication stress signaling and genome stability

  • Nucleic Acids Res. 2016 Oct 14;44(18):8772-8785. doi: 10.1093/nar/gkw615.
Giancarlo Barone 1,  Christopher J Staples 1,  Anil Ganesh 1,  Karl W Patterson 2,  Dominic P Bryne 3,  Katie N Myers 1,  Abhijit A Patil 1,  Claire E Eyers 3,  Sarah Maslen 4,  J Mark Skehel 4,  Patrick A Eyers 5,  Spencer J Collis 6
Affiliations

Affiliations

  • 1 Genome Stability Group, Sheffield Institute for Nucleic Acids (SInFoNiA), Academic Unit of Molecular Oncology, Department of Oncology & Metabolism, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
  • 2 DNA Replication and Repair Group, Sheffield Institute for Nucleic Acids (SInFoNiA), Academic Unit of Molecular Oncology, Department of Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
  • 3 Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
  • 4 Mass Spectrometry Group, The MRC Laboratory of Molecular Biology, Division of Cell Biology, Hills Road, Cambridge, CB2 0QH, UK.
  • 5 Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK patrick.eyers@liverpool.ac.uk.
  • 6 Genome Stability Group, Sheffield Institute for Nucleic Acids (SInFoNiA), Academic Unit of Molecular Oncology, Department of Oncology & Metabolism, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK s.collis@sheffield.ac.uk.
PMID: 27382066 DOI: 10.1093/nar/gkw615
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.

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