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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.

The exchange of replication-coupled canonical histones by histone variants endows chromatin with specific features. The replacement of the canonical H2A histone for the histone variant macroH2A is one of the most remarkable epigenetic modifications. The three vertebrate macroH2A proteins have a unique tripartite structure consisting of H2A-like domain, unstructured linker, and macrodomain. Macrodomains are ancient globular folds that are able to bind nicotinamide adenine dinucleotide (NAD(+)) derived metabolites. Here, we will briefly describe the physiological relevance of the metabolite binding in the context of chromatin. In particular, we will focus on the macroH2A1.1 isoform that binds ADP-ribose and poly-ADP-ribose polymerase 1 (PARP1) enzyme, a cellular stress sensor. We will discuss the impact of this interaction in the context of cancer, senescence, cell stress and energy metabolism.