A conserved NAD+ binding pocket that regulates protein-protein interactions during aging
DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate–ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.
The data show that NAD+ has a third function in cells: to directly regulate protein-protein interactions. We speculate that this mechanism evolved to allow a cell to adapt to fluctuations in NAD+ abundance without degrading it and, in the case of DBC1, to serve as a negative-feedback loop to prevent PARP1 from depleting NAD+ down to lethal levels during DNA damage (15) (fig. S19). The data also provide an explanation for why DBC1 mutations are associated with cancers (22) and indicate that assessing DBC1 status in tumors will help inform ongoing clinical trials of PARP1 inhibitors for treating cancer (23). Although the reason NAD+ declines with age is unclear, this work provides a plausible explanation for why DNA repair capacity declines as we age (24), pointing to NAD+ replenishment as a means of reducing the side effects of chemotherapy, protecting against radiation exposure, and slowing the natural decline in DNA repair capacity during aging.
