PIAS1/PIAS4-Mediated SUMOylation of TDP-43 Is Induced by Oxidative Stress

TAR DNA-binding protein 43 (TDP-43) is a conserved RNA and DNA binding protein that functions in transcriptional repression, pre-mRNA splicing and mRNA stabilization. Under pathological conditions found in multiple neurodegenerative diseases, TDP-43 shows aberrant mislocalization from the nucleus and cytoplasmic accumulation and aggregation. TDP-43 also appears to play a role in DNA damage repair, specifically in non-homologous end-joining (NHEJ), suggesting that nuclear depletion of TDP-43 may contribute towards the accumulation of DNA damage observed in TDP-43 proteinopathies. These TDP-43 pathological inclusions are decorated with post-translational modifications, most notably phosphorylation. SUMOylation (Small Ubiquitin-like Modifier) is a dynamic post-translational modification that regulates many protein properties and is implicated in neurodegenerative disease pathology. DNA damage repair proteins are commonly regulated through SUMOylation, and the SUMO E3 ligases PIAS1 and PIAS4 are required for efficient DNA repair of double-strand DNA breaks. Given these findings, we investigated TDP-43 SUMOylation and whether SUMO modification impacts TDP-43's DNA damage repair function. We show that TDP-43 can be modified by SUMO1 and SUMO2/3 and confirm SUMOylation in response to oxidative stress. We also determine which regions of TDP-43 are SUMOylated and show that this modification is facilitated by the SUMO E3 ligases PIAS1 and PIAS4. Etoposide-induced DNA damage did not promote SUMOylation of TDP-43; studies are ongoing to determine the impact of TDP-43 SUMOylation on DNA repair.