p16INK4a deficiency promotes DNA hyper‐replication and genetic instability in melanocytes |
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| Authors: | Carina Fung Gulietta M Pupo Richard A Scolyer Richard F Kefford Helen Rizos |
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| Institution: | 1. Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, , Westmead, NSW, Australia;2. Melanoma Institute Australia, , Sydney, NSW, Australia;3. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, , Sydney, NSW, Australia;4. Disciplines of Pathology, Sydney Medical School, The University of Sydney, , Sydney, NSW, Australia |
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| 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 p16INK4a 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 p16INK4a 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 p16INK4a expression co‐segregate closely. Thus, we propose that loss of p16INK4a facilitates tumourigenesis by promoting the proliferation of genetically unstable cells. |
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| Keywords: | p16INK4a melanoma DNA damage p53 |
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