Circular isoforms switch from repressors to activators of expression during RAF1 oncogene-induced senescence.

Long non-coding RNAs (ncRNAs) are major regulators of gene expression and cell fate. The locus encodes the tumour suppressor proteins p15, p16 and p14 required for cell cycle arrest and whose expression increases during senescence. is a ncRNA antisense to the gene. In proliferative cells, prevents senescence by repressing genes through the recruitment of Polycomb-group proteins. In models of replicative and RASval12 oncogene-induced senescence (OIS), the expression of and Polycomb proteins decreases, thus allowing derepression. Here, we found in a model of RAF1 OIS that expression rather increases, due in particular to an increased stability. This led us to search for circular isoforms, as circular RNAs are rather stable species. We found that the expression of two circular increases in several OIS models (RAF1, MEK1 and BRAF). In proliferative cells, they repress expression, while in RAF1 OIS, they promote full induction of and expression. Further analysis of one of these circular shows that it interacts with Polycomb proteins and decreases EZH2 Polycomb protein localization and H3K27me3 at the and promoters, respectively. We propose that changes in the ratio between Polycomb proteins and circular isoforms allow these isoforms to switch from repressors of gene to activators of all genes in RAF1 OIS. Our data reveal that regulation of expression depends on the senescence inducer and underline the importance of circular in the regulation of gene expression and senescence.