P53 status determines the epigenetic response to demethylating agents azacitidine and decitabine.

ABSTRACT: 5'-Azacitidine (Aza) and 5-Aza-2'-deoxycytidine (Dac) are widely used demethylating drugs that directly integrate into nucleic acids. They are frequently used interchangeably, surprisingly as their selectivity is unique from the other, with no predictors of response or clinical biomarkers to indicate drug preference. Using these drugs to induce demethylation, we combine DRIPc-Seq, Immunostaining, RNA-Seq and Mass spectrometry to uncover unique cellular responses. Activation of p53, exclusively by Aza, sustains accumulation of R-loops in CpG islands of p53 target genes. This effect is abolished by the removal of p53, compounded by destabilisation of heterochromatin marks. Dac treatment induces global chromatin modification, sustaining DNA damage, which is heightened in the absence of p53. R

SUBMITTER: Hands EL 

PROVIDER: S-EPMC12936189 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature