Methylation of the Suppressor Gene p16INK4a : Mechanism and Consequences

Alfonso TramontanoAntonio Pezone


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.


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Related Concepts

Malignant Neoplasms
DNA Damage
Gene Deletion
Promoter Regions, Genetic
Transcription, Genetic
Transformation, Genetic
Tumor Suppressor Genes
Mts2 endopeptidase protein

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