p16^INK4a deficiency promotes DNA hyper-replication and genetic instability in melanocytes

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^INK4a 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^INK4a 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^INK4a expression co-segregate closely. Thus, we propose that loss of p16^INK4a facilitates tumourigenesis by promoting the proliferation of genetically unstable cells.