Gueldenpfennig, AnkaHopp, Ann-KatrinMuskalla, LukasManetsch, PatrickRaith, FabioHellweg, LarsDoerdelmann, CyrilPedrioli, Deena M. LeslieJohnsson, KaiSuperti-Furga, GiulioHottiger, Michael O.2023-08-282023-08-282023-08-282023-08-1710.1093/nar/gkad659https://infoscience.epfl.ch/handle/20.500.14299/200259WOS:001049087200001Though 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.Biochemistry & Molecular Biologyadp-ribosylationdamageparp1compartmentationexpressionintegritycancerrolescellsfocustext::journal::journal article::research article