Methylation of the Suppressor Gene <i>p16INK4a</i>: Mechanism and Consequences
Alfonso Tramontano,
Francesca Ludovica Boffo,
Giusi Russo,
Mariarosaria De Rosa,
Ilaria Iodice,
Antonio Pezone
Affiliations
Alfonso Tramontano
Department of Precision Medicine University of Campania “L. Vanvitelli”, 80131 Naples, Italy
Francesca Ludovica Boffo
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R., Università Federico II, 80131 Napoli, Italy
Giusi Russo
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R., Università Federico II, 80131 Napoli, Italy
Mariarosaria De Rosa
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R., Università Federico II, 80131 Napoli, Italy
Ilaria Iodice
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R., Università Federico II, 80131 Napoli, Italy
Antonio Pezone
Department of Precision Medicine University of Campania “L. Vanvitelli”, 80131 Naples, Italy
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.
