Viral cyclin-cyclin-dependent kinase 6 complexes initiate nuclear DNA replication.
The cyclins encoded by Kaposi sarcoma-associated herpesvirus and herpesvirus saimiri are homologs of human D-type cyclins. However, when complexed to cdk6, they have several activities that distinguish them from D-type cyclin-cdk6 complexes, including resistance to cyclin-dependent kinase inhibitors and an enhanced substrate range. We find that viral cyclins interact with and phosphorylate proteins involved in replication initiation. Using mammalian in vitro replication systems, we show that viral cyclin-cdk6 complexes can directly trigger the initiation of DNA synthesis in isolated late-G(1)-phase nuclei. Viral cyclin-cdk6 complexes share this capacity with cyclin A-cdk2, demonstrating that in addition to functioning as G(1)-phase cyclin-cdk complexes, they function as S-phase cyclin-cdk complexes.
Laman
H
H
Gene Regulation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom.
Coverley
D
D
Krude
T
T
Laskey
R
R
Jones
N
N
D016475:3T3 Cells; D000818:Animals; D042846:CDC2-CDC28 Kinases; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D016193:G1 Phase; D006564:Herpesviridae / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D051738:Origin Recognition Complex; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D016196:S Phase; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism*
C113028:CCNK protein, human; D019927:Cyclin E; D016213:Cyclins; D004268:DNA-Binding Proteins; D051738:Origin Recognition Complex; D011518:Proto-Oncogene Proteins; D011687:Purines; D014764:Viral Proteins; D000077546:Roscovitine; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases