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Updated: May 15, 2026

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
p16(INK) (4a) deficiency promotes DNA hyper-replication and genetic instability in melanocytes
Carina Fung1, Gulietta M Pupo, Richard A Scolyer
1Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Australia.
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.
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