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

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

Author information

1
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany.
3
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
4
Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
5
Division of Biology, 434 Hutchinson Hall, River Campus, University of Rochester, Rochester, NY 14627, USA.
6
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA. david_sinclair@hms.harvard.edu.
7
Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia.

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.

PMID:
28336669
PMCID:
PMC5456119
DOI:
10.1126/science.aad8242
[Indexed for MEDLINE]
Free PMC Article

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