A new mechanism of inactivation of the INK4/ARF locus.

The INK4/ARF locus encodes three tumor suppressors, p15(INK4b), p16(INK4a) and ARF, which together constitute one of the main anti-oncogenic defenses of mammalian organisms. The activity of these tumor suppressors depends mostly on the transcriptional status of the locus. Recently, we have identified a conserved DNA element with the capacity to regulate the locus in a global manner. Inactivation of this element, which we have named RD(INK4/ARF), results in the silencing of the entire INK4/ARF locus. Interestingly, RD(INK4/ARF) is both a transcriptional regulatory element and a replication origin. The replication protein Cdc6 binds to RD(INK4/ARF) and is able to recruit histone deacetylases that, in turn, result in the heterochromatinization and repression of the INK4/ARF locus. This model has striking parallelisms with the silencing of the yeast mating-type loci, and it is a novel oncogenic mechanism that connects the replication machinery with the inactivation of tumor suppressors.