A Conserved NAD + Binding Pocket That Regulates Protein-Protein Interactions During Aging

Science. 2017 Mar 24;355(6331):1312-1317. doi: 10.1126/science.aad8242.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Conserved Sequence
  • DNA Damage / genetics
  • DNA Repair*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Models, Molecular
  • NAD / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Paraquat / pharmacology
  • Poly (ADP-Ribose) Polymerase-1 / chemistry
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Poly (ADP-Ribose) Polymerase-1 / metabolism*
  • Protein Interaction Domains and Motifs
  • RNA, Small Interfering / genetics
  • Radiation Tolerance / genetics
  • Sequence Homology, Nucleic Acid

Substances

  • Adaptor Proteins, Signal Transducing
  • CCAR2 protein, human
  • RNA, Small Interfering
  • NAD
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Paraquat