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p16 INK 4a deficiency promotes DNA hyper‐replication and genetic instability in melanocytes
Author(s) -
Fung Carina,
Pupo Gulietta M.,
Scolyer Richard A.,
Kefford Richard F.,
Rizos Helen
Publication year - 2013
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12062
Subject(s) - dna replication , dna damage , biology , dna , microbiology and biotechnology , genome instability , cell growth , melanoma , g2 m dna damage checkpoint , cell cycle , cancer research , cell cycle checkpoint , cell , genetics
Summary 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.