Methylation of the Suppressor Gene p16INK4a: Mechanism and Consequences

Biomolecules. 2020 Mar 13;10(3):446. doi: 10.3390/biom10030446.

Abstract

Tumor suppressor genes in the CDKN2A/B locus (p15INK4b, p16INK4a, and p14ARF) function as biological barriers to transformation and are the most frequently silenced or deleted genes in human cancers. This gene silencing frequently occurs due to DNA methylation of the promoter regions, although the underlying mechanism is currently unknown. We present evidence that methylation of p16INK4a promoter is associated with DNA damage caused by interference between transcription and replication processes. Inhibition of replication or transcription significantly reduces the DNA damage and CpGs methylation of the p16INK4a promoter. We conclude that de novo methylation of the promoter regions is dependent on local DNA damage. DNA methylation reduces the expression of p16INK4a and ultimately removes this barrier to oncogene-induced senescence.

Keywords: DNA damage and repair; DNA methylation; gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cellular Senescence
  • CpG Islands*
  • Cyclin-Dependent Kinase Inhibitor p16* / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p16* / genetics
  • DNA Damage
  • DNA Methylation*
  • DNA Replication*
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Humans
  • Promoter Regions, Genetic*

Substances

  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16