Absence of mitochondrial SLC25A51 enhances PARP1-dependent DNA repair by increasing nuclear NAD+ levels

作者：Anka Güldenpfennig, Ann-Katrin Hopp, Lukas Muskalla, Patrick Manetsch, Fabio Raith, Lars Hellweg, Cyril Dördelmann, Deena M. Leslie Pedrioli, Kai Johnsson, Giulio Superti‐Furga, Michael O. Hottiger · 发表于：Nucleic Acids Research · 年份：2023 · DOI：10.1093/nar/gkad659 · 被引用次数：29 · 研究领域：PARP inhibition in cancer therapy、DNA Repair Mechanisms、Electrostatic Discharge in Electronics

Though the effect of the recently identified mitochondrial NAD+ transporter SLC25A51 on glucose metabolism has been described, its contribution to other NAD+-dependent processes throughout the cell such as ADP-ribosylation remains elusive. Here, we report that absence of SLC25A51 leads to increased NAD+ concentration not only in the cytoplasm and but also in the nucleus. The increase is not associated with upregulation of the salvage pathway, implying an accumulation of constitutively synthesized NAD+ in the cytoplasm and nucleus. This results in an increase of PARP1-mediated nuclear ADP-ribosylation, as well as faster repair of DNA lesions induced by different single-strand DNA damaging agents. Lastly, absence of SLC25A51 reduces both MMS/Olaparib induced PARP1 chromatin retention and the sensitivity of different breast cancer cells to PARP1 inhibition. Together these results provide evidence that SLC25A51 might be a novel target to improve PARP1 inhibitor based therapies by changing subcellular NAD+ redistribution.