title: p16(INK)             (4a)  deficiency promotes DNA hyper-replication and genetic instability in melanocytes.
abstract: Activated oncogenes restrict cell proliferation and transformation by triggering a DNA damage-dependent senescence checkpoint in response to DNA hyper-replication. Here, we show that loss of the p16(INK)             (4a)  cyclin-dependent kinase inhibitor and melanoma tumour suppressor facilitates a DNA damage response after a hyper-replicative phase in human melanocytes. Unlike cells expressing activated oncogenes, however, melanocytes depleted for p16(INK)             (4a)  display enhanced proliferation and an extended replicative lifespan in the presence of replication-associated DNA damage. Analysis of human benign naevi confirmed that DNA damage and loss of p16(INK)             (4a)  expression co-segregate closely. Thus, we propose that loss of p16(INK)             (4a)  facilitates tumourigenesis by promoting the proliferation of genetically unstable cells.
authors.affiliation: Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.
authors.forename: Carina
authors.initials: C
authors.lastname: Fung
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication; D042822:Genomic Instability; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008544:Melanocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009506:Nevus / Q000378:metabolism / Q000473:pathology; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C468783:H2AX protein, human; D006657:Histones; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D018844:Cyclin-Dependent Kinases