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.
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
Jun
0000-0002-0179-4151
J
Li
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
Michael S
MS
Bonkowski
Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany.
Sébastien
S
Moniot
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
Dapeng
D
Zhang
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
Basil P
BP
Hubbard
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
Alvin J Y
0000-0001-5798-9495
AJ
Ling
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
Luis A
0000-0003-4106-4230
LA
Rajman
Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
Bo
B
Qin
Division of Oncology Research, Department of Oncology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
Zhenkun
Z
Lou
Division of Biology, 434 Hutchinson Hall, River Campus, University of Rochester, Rochester, NY 14627, USA.
Vera
V
Gorbunova
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
L
L
Aravind
Department of Biochemistry, University of Bayreuth, 95440 Bayreuth, Germany.
Clemens
C
Steegborn
Department of Genetics, Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA. david_sinclair@hms.harvard.edu.|Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney, New South Wales 2052, Australia.
David A
0000-0002-9936-436X
DA
Sinclair
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017124:Conserved Sequence; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009243:NAD / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D010269:Paraquat / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid
D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D034741:RNA, Small Interfering; D009243:NAD; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D010269:Paraquat