TY - JOUR
T1 - A conserved NAD+ binding pocket that regulates protein-protein interactions during aging
AU - Li, Jun
AU - Bonkowski, Michael S.
AU - Moniot, Sébastien
AU - Zhang, Dapeng
AU - Hubbard, Basil P.
AU - Ling, Alvin J.Y.
AU - Rajman, Luis A.
AU - Qin, Bo
AU - Lou, Zhenkun
AU - Gorbunova, Vera
AU - Aravind, L.
AU - Steegborn, Clemens
AU - Sinclair, David A.
N1 - Funding Information:
D.A.S. was supported by the Glenn Foundation for Medical Research, American Federation for Aging Research, E. Schulak, and grants from the National Institute on Aging and the NIH; D.Z. and L.A. by the National Library of Medicine/NIH intramural program; and C.S. by Deutsche Forschungsgemeinschaft (STE1701/15). Z.L. was supported by grants CA130996 and CA203561 from the National Cancer Institute and J.L. by the Sinclair Harvard Fund.
PY - 2017/3/24
Y1 - 2017/3/24
N2 - 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.
AB - 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.
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U2 - 10.1126/science.aad8242
DO - 10.1126/science.aad8242
M3 - Article
C2 - 28336669
AN - SCOPUS:85016317809
SN - 0036-8075
VL - 355
SP - 1312
EP - 1317
JO - Science
JF - Science
IS - 6331
ER -