Circular ANRIL isoforms switch from repressors to activators of p15/CDKN2B expression during RAF1 oncogene-induced senescence
The ANRIL ncRNA is produced as an antisense RNA to the p15 -encoding gene from the INK4 locus, which encodes three tumor suppressor proteins required for cell cycle arrest, p15 INK4b , p16 INK4a and p14 ARF . In proliferative cells, ANRIL prevents cellular senescence by repressing the expression of INK4 genes through Polycomb protein recruitment. Decreased expression of ANRIL in senescence is thought to relieve this repression. Here, we observe in various models of oncogene-induced senescence
... nduced senescence that senescence induction is accompanied by an increase in ANRIL expression, including the increase of circular ANRIL species. Circular ANRIL species repress p15 gene expression in proliferative cells as previously described for ANRIL . However, in RAF1 oncogene-induced senescent cells, circular ANRIL isoforms are required for full induction of p15 , p16 and p14 ARF gene expression . They interact with Polycomb group proteins and regulate H3K27me3 at the p16 gene promoter. Hence, we propose a mechanism relying on changes in the ratio between circular ANRIL and Polycomb proteins by which circular ANRIL species switch from being repressors of p15 expression to activators of INK4 gene expression during RAF1-induced senescence. Our data highlight the functional importance of the ratio between ncRNAs and their interacting effectors in the control of cell fate progression.