尽管我们已经描述了最近发现的线粒体NAD+转运蛋白SLC25A51对葡萄糖代谢的影响，但其对细胞中其他依赖NAD+的过程如ADP-核糖基化的贡献仍然不明确。在这里，我们报道了SLC25A51缺失导致细胞质和细胞核中NAD+浓度的增加。这种增加与救赎途径的上调无关，暗示细胞质和细胞核中NAD+的持续合成导致其积累。这导致PARP1介导的核部位ADP-核糖基化增加，并且通过不同单链DNA损伤剂诱导的DNA损伤修复更快。最后，SLC25A51缺失降低了对MMS/Olaparib诱导的PARP1染色质富集和不同乳腺癌细胞对PARP1抑制剂的敏感性。综上所述，这些结果提供了证据表明SLC25A51可能是通过改变亚细胞NAD+重分布来改善PARP1抑制剂治疗的新靶点。© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

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.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.