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

Highlights: What are the main findings? DJ-1/PARK7 modulates the transcriptional response to X-ray-induced DNA damage, linking redox regulation to genome stability. Following X-ray irradiation, DJ-1 overexpression leads to coordinated suppression of the translation machinery and mitochondria, while DJ-1 knockdown disrupts global transcriptional homeostasis. What are the implications of the main findings? DJ-1 acts as a key factor during genotoxic stress, integrating transcriptional coding and non-coding RNA networks. Understanding DJ-1-dependent pathways may support the development of targeted strategies to enhance maintaining genomic integrity. 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 under varying DJ-1 expression levels. Using siRNA knockdown and overexpression approaches, transcriptional changes were analyzed by RNA-seq. Naïve cells exhibited only a moderate response to X-ray exposure, including suppression of the cell cycle and activation of stress pathways. In contrast, DJ-1 overexpression caused pronounced gene-expression suppression, particularly affecting ribosomal genes and mitochondria, with 21- and 3.5-fold enrichment, respectively. DJ-1 knockdown led to extensive, non-specific transcriptional changes affecting ~18% of all transcripts (~3400), indicating disrupted cellular homeostasis. Under DJ-1 knockdown, X-ray irradiation resulted in a 3.7-fold enrichment of suppressed DNA-damage response genes. Notably, approximately 25% of non-coding RNAs (ncRNAs) were differentially expressed following DJ-1 manipulation. X-ray-irradiated cells with DJ-1 overexpression also showed reduced expression of SNHG lncRNAs that host snoRNAs, potentially altering miRNA-sponging capacity and ribosomal regulation. These findings underscore DJ-1’s critical role in modulating cellular responses to genotoxic stress, reshaping transcriptional landscapes, and regulating ncRNA profiles. The dual impact of DJ-1 on redox and transcriptional networks positions it as a potential therapeutic target in diseases involving oxidative stress and impaired DNA repair.