The taming of PARP1 and its impact on NAD+ metabolism

Background: Poly-ADP-ribose polymerases (PARPs) are key mediators of cellular stress response. They are intimately linked to cellular metabolism through the consumption of NAD+. PARP1/ARTD1 in the nucleus is the major NAD+ consuming activity and plays a key role in maintaining genomic integrity. Scope of review: In this review, we discuss how different organelles are linked through NAD+ metabolism and how PARP1 activation in the nucleus can impact the function of distant organelles. We discuss how differentiated cells tame PARP1 function by upregulating an endogenous inhibitor, the histone variant macroH2A1.1. Major conclusions: The presence of macroH2A1.1, particularly in differentiated cells, raises the threshold for the activation of PARP1 with consequences for DNA repair, gene transcription, and NAD+ homeostasis. Research in the Ladurner and Buschbeck labs was supported by the following grants: the Deutsche Forschungsgemeinschaft SFB 646 and SFB 1064 collaborative research centers (to AGL); the Deutsche Forschungsgemeinschaft CIPSM and SyNergy research excellence clusters (to AGL); the Bavarian BioSysNet Program (to AGL); the ERA-NET Neuron project Food4Thought funded by the Bundesministerium für Bildung und Forschung (to AGL); the Marie Skłodowska Curie Training network “ChroMe” H2020-MSCA-ITN-2015-675,610 (to MB and AGL); MINECO RTI2018-094005-B-I00 (to MB); MINECO-ISCIII PIE16/00011 (to MB); the Deutsche José Carreras Leukaemie Stiftung DJCLS 14R/2018 (to MB); AGAUR 2017-SGR-305 (to MB); and Fundació La Marató de TV3 257/C/2019 (to MB). Research at the IJC is supported by the La Caixa Foundation, the Fundació Internacional Josep Carreras, Celgene Spain, and the CERCA Program/Generalitat de Catalunya.