DJ-1/PARK7 Determines miRNA Network Plasticity During Genotoxic Stress

<jats:p>PARK7 (DJ-1) is a redox-sensitive protein that supports cellular adaptation, but its role in post-transcriptional responses to genotoxic stress remains unclear. We investigated whether DJ-1 abundance determines the miRNA response to X-ray-induced DNA damage. Integrated mRNA-seq and small RNA-seq across DJ-1 states in HEK293 cells revealed a striking divergence in miRNA plasticity. DJ-1 depletion produced minimal miRNA remodeling, with only 34 (6.3%) miRNAs differentially expressed after irradiation. In contrast, elevated DJ-1 markedly increased miRNA plasticity. Irradiation altered ~37% of the miRNAs, and ~90% of the reads. DJ-1 overexpression was also associated with altered miRNA regulatory machinery, particularly components involved in miRNA sorting and stability. Comparison of precursor and mature species revealed substantial uncoupling between transcription and miRNA abundance, implicating regulation at the levels of processing, maturation, or stability. Radiation-responsive genes in DJ-1-overexpressing cells were relatively depleted of miRNA binding sites, supporting preferential regulation of upstream factors rather than the bulk transcriptome. Together, these findings identify DJ-1 as a determinant of post-transcriptional signaling plasticity, enabling dynamic remodeling of miRNA regulatory state in response to genotoxic stress.</jats:p>