p16INK4a deficiency promotes DNA hyper-replication and genetic instability in melanocytes

Carina Fung, Gulietta M. Pupo, Richard A. Scolyer, Richard F. Kefford, Helen Rizos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)236-246
Number of pages11
JournalPigment Cell and Melanoma Research
Volume26
Issue number2
DOIs
Publication statusPublished - Mar 2013
Externally publishedYes

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