title: Human CDK18 promotes replication stress signaling and genome stability.
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.
authors.affiliation: 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.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Barone
authors.affiliation: 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.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Staples
authors.affiliation: 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.
authors.forename: Anil
authors.initials: A
authors.lastname: Ganesh
authors.affiliation: 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.
authors.forename: Karl W
authors.initials: KW
authors.lastname: Patterson
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Bryne
authors.affiliation: 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.
authors.forename: Katie N
authors.initials: KN
authors.lastname: Myers
authors.affiliation: 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.
authors.forename: Abhijit A
authors.initials: AA
authors.lastname: Patil
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Eyers
authors.affiliation: Mass Spectrometry Group, The MRC Laboratory of Molecular Biology, Division of Cell Biology, Hills Road, Cambridge, CB2 0QH, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Maslen
authors.affiliation: Mass Spectrometry Group, The MRC Laboratory of Molecular Biology, Division of Cell Biology, Hills Road, Cambridge, CB2 0QH, UK.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Skehel
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK patrick.eyers@liverpool.ac.uk.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Eyers
authors.affiliation: 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.
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Collis
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D042822:Genomic Instability; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D034741:RNA, Small Interfering; D018844:Cyclin-Dependent Kinases; C089464:PCTAIRE-3 protein kinase