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The enzymes of the base excision repair (BER) pathway form DNA lesion-dependent, transient complexes that vary in composition based on the type of DNA damage. These protein sub-complexes facilitate substrate/product handoff to ensure reaction completion so as to avoid accumulation of potentially toxic DNA repair intermediates. However, in the mammalian cell, additional signaling molecules are required to fine-tune the activity of the BER pathway enzymes and to facilitate chromatin/histone reorganization for access to the DNA lesion for repair. These signaling enzymes include nicotinamide adenine dinucleotide (NAD⁺) dependent poly(ADP-ribose) polymerases (PARP1, PARP2) and class III deacetylases (SIRT1, SIRT6) that comprise a key PARP-NAD-SIRT axis to facilitate the regulation and coordination of BER in the mammalian cell. Here, we briefly describe the key nodes in the BER pathway that are …