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A New Mechanism of Inactivation of the INK4/ARF Locus
Susana Gonzalez and Manuel Serrano
volume 5 | issue 13
1 july 2006Pages: 1382 - 1384
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The INK4/ARF locus encodes three tumor suppressors, p15INK4b, p16INK4a, and ARF, and is 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 ability to regulate the locus in a global manner. Inactivation of this element, which we have named RDINK4/ARF, results in the silencing of the entire INK4/ARF locus. Interestingly, RDINK4/ARF is both a transcriptional regulatory element and a replication origin. The replication protein Cdc6 binds to RDINK4/ARF and is able to recruit histone deacetylases that 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. Finally, it constitutes a novel oncogenic mechanism that connects the replication machinery with the inactivation of tumor suppressors.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.