Manipulating PARK7/DJ-1 Levels by Genotoxic Stress Alters Noncoding RNAs and Cellular Homeostasis

DJ-1/PARK7 is a multifunctional protein that plays a vital role in sensing oxidative stress and maintaining redox homeostasis. As an oncogene, DJ-1 influences p53-mediated stress responses and contributes to cancer progression. This study investigates the impact of X-ray-induced DNA breaks on cellular responses post-irradiation under varying DJ-1 expression levels. Using siRNA knockdown and overexpression to modulate DJ-1 levels, transcriptional changes were analyzed through RNA-seq. Naive cells exhibited only a moderate transcriptional response to X-ray exposure, including suppression of the cell cycle and activation of stress pathways. Overexpression of DJ-1 led to pronounced gene expression suppression, particularly suppression of most ribosomal and mitochondrial genes. Conversely, DJ-1 knockdown caused extensive, non-specific transcriptional changes, indicating disrupted cellular homeostasis. Notably, around 25% of non-coding RNAs were differentially expressed under these conditions. DJ-1 overexpression suppressed lncRNA of the host genes for snoRNAs, thus altering the miRNA sponging capacity after X-ray exposure. These findings underscore DJ-1s critical role in modulating cellular responses to genotoxic stress, reshaping transcriptional landscapes, and regulating non-coding RNA profiles. DJ-1 emerges as essential for maintaining genomic stability.