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These findings suggest that at least at PUMA and MDM2, high levels of p53 may inhibit stress-induced antisense transcription and promote sense transcription, thereby regulating sense/antisense ratios. A similar mechanism may be in play at p21 but with additional p53-independent contributions. Thus, p53 levels may affect the expression of coding genes in part through effects on antisense transcription. This assessment is based on general trends of p53 levels occurring across distinct cancer cell lines and within the same cell line and, thus, complicated by cell-type-specific effects. To directly address the role of antisense in regulating sense expression, p21 antisense transcripts Mianserin HCl were knocked down in U2OS cells by small interfering RNA (siRNA), then tested for p21 sense induction by UV stress. We observed an increase in levels of p21 protein in comparison to a scrambled siRNA control ( Figure?5D). This suggests that UV-induced p21 antisense RNA downregulates p21 sense expression, in accord with a prior report demonstrating that UV stress leads to reduction of p21 in preparation for apoptosis ( Bendjennat et?al., 2003). It also fits with the more general notion that p53-regulated noncoding RNA (ncRNA) promotes gene repression globally ( Huarte et?al., 2010?and?Mar��n-B��jar Ferroptosis inhibitor review et?al., 2013). Taken together, these findings suggest a tandem repression mechanism for regulating p21 expression, where stress-induced antisense transcripts attenuate stress-induced sense expression. High levels of p53 may inhibit antisense production, thereby allowing full sense gene activation (which may also have direct contributions from p53 and other factors). How general this mechanism is remains to be determined because not all stress-induced antisense transcription is accompanied by a corresponding reduction of sense transcription ( Figure?5B). In an effort to link p53 and stress with mechanisms of gene regulation, we initially narrowed in on a filtered set of 751 ��active�� genes (annotated TSSs having stringently defined TFIIB, and also being Sirolimus solubility dmso Procedures for details and Table S4). UV treatment of U2OS cells generally had little effect on TFIIB occupancy at these genes, which was surprising because recruitment of initiation factors has been considered as one basis for gene induction (Ma, 2011?and?Ptashne and Gann, 1997). In contrast, Pol II was released from where it normally pauses at the 5�� ends of genes and increased in gene bodies, which is in accord with models on heat shock induction (Figure?S6A) (Rougvie and Lis, 1988). We cannot exclude the possibility that at least some of the Pol II is lost due to UV-induced degradation. Related observations of Pol II release were reported at the p53-regulated Fas and p21 genes (Espinosa et?al., 2003?and?Gomes et?al.