Human CDK18 promotes replication stress signaling and genome stability

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  • Giancarlo Barone
    University of Sheffield
  • Christopher J Staples
    University of Sheffield
  • Anil Ganesh
    University of Sheffield
  • Karl W Patterson
    University of Sheffield
  • Dominic P Bryne
    University of Liverpool
  • Katie N Myers
    University of Sheffield
  • Abhijit A Patil
    University of Sheffield
  • Claire E Eyers
    University of Liverpool
  • Sarah Maslen
    Mass Spectrometry Group, Cambridge
  • J Mark Skehel
    Mass Spectrometry Group, Cambridge
  • Patrick A Eyers
    University of Liverpool
  • Spencer J Collis
    University of Sheffield

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.

Original languageEnglish
Pages (from-to)8772-8785
Number of pages14
JournalNucleic Acids Research
Issue number18
Early online date5 Jul 2016
Publication statusPublished - 14 Oct 2016
Externally publishedYes

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