Deregulated G1-cyclin expression induces genomic instability by preventing efficient pre-RC formation.
Although genomic instability is a hallmark of human cancer cells, the mechanisms by which genomic instability is generated and selected for during oncogenesis remain obscure. In most human cancers, the pathway leading to the activation of the G1 cyclins is deregulated. Using budding yeast as a model, we show that overexpression of the G1 cyclin Cln2 inhibits the assembly of prereplicative complexes (pre-RCs) and induces gross chromosome rearrangements (GCR). Our results suggest that deregulation of G1 cyclins, selected for in oncogenesis because it confers clonal growth advantage, may also provide an important mechanism for generating genomic instability by inhibiting replication licensing.
Tanaka
Seiji
S
Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK.
Diffley
John F X
JF
D002453:Cell Cycle / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone; D002869:Chromosome Aberrations; D015825:Chromosomes, Fungal; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056746:Cyclin G; D056766:Cyclin G1; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D018983:DNA Footprinting; D004261:DNA Replication / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005656:Fungal Proteins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D009693:Nucleic Acid Hybridization; D010957:Plasmids; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D000091346:Tripeptidyl-Peptidase 1
C534702:CCNG1 protein, human; C082721:CLN2 protein, S cerevisiae; D002868:Chromosomal Proteins, Non-Histone; D019926:Cyclin B; D056746:Cyclin G; D056766:Cyclin G1; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D016213:Cyclins; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; C086926:SIC1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000091346:Tripeptidyl-Peptidase 1; C069199:MCM2 protein, S cerevisiae