p16(INK) (4a) deficiency promotes DNA hyper-replication and genetic instability in melanocytes

Pigment Cell Melanoma Res. 2013 Mar;26(2):236-46. doi: 10.1111/pcmr.12062. Epub 2013 Jan 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / genetics
  • Cell Proliferation
  • Cyclin-Dependent Kinase Inhibitor p16 / deficiency*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Cyclin-Dependent Kinases / metabolism
  • DNA Damage / genetics
  • DNA Replication*
  • Genomic Instability*
  • HEK293 Cells
  • Histones / metabolism
  • Humans
  • Melanocytes / enzymology
  • Melanocytes / metabolism*
  • Melanocytes / pathology*
  • Nevus / metabolism
  • Nevus / pathology
  • Retinoblastoma Protein / metabolism
  • Tumor Suppressor Protein p53 / metabolism


  • Cyclin-Dependent Kinase Inhibitor p16
  • H2AX protein, human
  • Histones
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Cyclin-Dependent Kinases