Methylation of the Suppressor Gene p16INK4a: Mechanism and Consequences

Abstract

Tumor suppressor genes in the <i>CDKN2A/B</i> locus (<i>p15INK4b</i>, <i>p16INK4a</i>, and <i>p14ARF</i>) 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 <i>p16INK4a</i> 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 <i>p16INK4a</i> promoter. We conclude that de novo methylation of the promoter regions is dependent on local DNA damage. DNA methylation reduces the expression of <i>p16INK4a</i> and ultimately removes this barrier to oncogene-induced senescence.