Epigenetic remodeling during UV exposure: high resolution analysis of histone post-translational modifications in a DNA binding protein 2 mutant model

Chromatin contains genetic information in eukaryotes. Multiple epigenetic mechanisms, such as chemical modifications of DNA and histone post-translational modifications (PTMs), regulate chromatin organization and architecture, influencing RNA transcription and driving diverse gene expression patterns from the same genome. This epigenetic control is highly dynamic and influenced by various events, such as DNA insults which cause altered gene expressions to drive aging, neurodegeneration, and cancer. However, this interplay remains poorly understood and identifying novel molecular effectors may shed light for therapeutic purposes. Here, we investigate the consequences of UV exposure in cells expressing a mutant form of damage-specific DNA-binding protein 2 (DDB2), a key protein for UV damage repair, in which interaction with PCNA is disrupted, thereby impairing proper DDB2 degradation. Our data reports that overexpression of mutant DDB2 resulted in persistent epigenetic alterations after UV irradiation, which led to elevated detection of H3K9 acetylation and trimethylation, as well as increments in 5-methylcytosine and altered subnuclear localization of γ-H2AX. Collectively, these findings demonstrate that DDB2-PCNA interaction regulates not only DDB2 stability, but also the epigenetic landscape of the genome.