A conserved NAD ⁺ binding pocket that regulates protein-protein interactions during aging

Abstract

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.

Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence

“…For example, the deleted in breast cancer protein 1 (DBC1) binds to and inhibits both SIRT1 and PARP1, the latter of which is dependent on NAD + binding to the “Nudix Homology Domain” (NHD) of DBC1 (Li et al, 2017). SIRT6 modifies PARP1 by mono-ADP-ribosylation, thereby increasing double strand DNA break (DSB) repair (Mao et al, 2011) whereas inhibition of PARP1 increases expression of SIRT1, SIRT4 and SIRT6 (Wencel et al, 2017).…”

“…Increased NAD + would also boost the activity of SIRT1 and SIRT6, both of which can inhibit tumors by downregulating beta-catenin signaling and glycolysis (Firestein et al, 2008; Sebastian et al, 2012). One concern is that raising NAD + may promote DNA repair and angiogenesis, helping cancer cells thrive (Batra and Kislay, 2013; Fang et al, 2016; Li et al, 2017). Long-term studies of wildtype mice, however, failed to provide any evidence of increased tumor size or number (Shukla et al, 2014; Tummala et al, 2014).…”

Sirtuins and Accelerated Aging in Scleroderma

“…Aging is associated with cumulative damage to macromolecules (DNA and protein) resulting from a decline in DNA and protein repair mechanisms [24–26] as well as increased reactive oxygen species (ROS) driven by mitochondrial dysfunction, cellular inflammatory responses, and functional impairment of proteolytic systems [27, 28]. Oxidative stress is increased in SSc [29] and contributes to fibrosis in SSc and IPF through multiple mechanisms involving oxidative protein and DNA damage [30, 31].…”

“…NAD, the oxidized form of nicotinamide adenine dinucleotide, extends lifespan in yeast [35], restores glucose tolerance in aged mice [36], and was recently shown to increase mouse lifespan as well as muscle stem cell number, muscle regeneration, and mitochondrial function in aged mice [37]. NAD declines during aging, and its restoration mediates protein-protein interactions required for DNA repair [26]. Siglecs, sialic acid-binding immunoglobulin-like receptors expressed by immune cells, block pro-inflammatory cascades and when deficient in mice, result in increased oxidative damage, reduced lifespan, and premature aging phenotypes [27].…”

Overexpression of Nmnat3 efficiently increases NAD and NGD levels and ameliorates age‐associated insulin resistance

“…Thus, NAD is considered a critical determinant of ATP and ROS production in the mitochondria (Murphy, 2009). Furthermore, NAD is a substrate for poly(ADP‐ribose) polymerase (PARP) and sirtuins, which catalyze ADP‐ribosylation and deacetylation, respectively (Canto, Menzies, & Auwerx, 2015; Li et al., 2017). Sirtuins are well‐known antiaging molecules with diverse biological functions in metabolism, gene expression, and cellular stress responses.…”