Methylation of the Suppressor Gene p16INK4a: Mechanism and Consequences

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 u...

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Detalles Bibliográficos
Autores principales: Tramontano, Alfonso, Boffo, Francesca Ludovica, Russo, Giusi, De Rosa, Mariarosaria, Iodice, Ilaria, Pezone, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Brief Report
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175352/
https://www.ncbi.nlm.nih.gov/pubmed/32183138
http://dx.doi.org/10.3390/biom10030446
Descripción
Sumario: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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