Department of Molecular Mechanisms of Disease (DMMD), University of Zurich, 8057 Zurich, Switzerland.
Life Science Zurich Graduate School, Molecular Life Science Ph.D. Program, University of Zurich, 8057 Zurich, Switzerland.
Nucleic Acids Res. 2023 Sep 22;51(17):9248-9265. doi: 10.1093/nar/gkad659.
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.
虽然最近鉴定的线粒体 NAD+转运体 SLC25A51 对葡萄糖代谢的影响已经被描述，但它对细胞内其他 NAD+依赖过程（如 ADP-核糖基化）的贡献仍然难以捉摸。在这里，我们报告说，SLC25A51 的缺失不仅导致细胞质中 NAD+浓度增加，而且导致细胞核中 NAD+浓度增加。这种增加与补救途径的上调无关，这意味着细胞质和细胞核中持续合成的 NAD+的积累。这导致 PARP1 介导的核 ADP-核糖基化增加，以及由不同的单链 DNA 损伤剂诱导的 DNA 损伤的更快修复。最后，SLC25A51 的缺失减少了 MMS/Olaparib 诱导的 PARP1 染色质保留以及不同乳腺癌细胞对 PARP1 抑制的敏感性。这些结果共同表明，SLC25A51 可能是通过改变细胞内亚 NAD+重新分布来改善基于 PARP1 抑制剂的治疗的新靶点。
