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

NAD+ can influence DNA repair by modulating protein interactions. NAD+ binding modulates protein interactions An unexpected function of the oxidized form of nicotinamide adenine dinucleotide (NAD+) could underlie some effects of aging and propensity to age-related diseases. Li et al. found that the protein DBC1 (deleted in breast cancer 1) contains a domain that specifically binds NAD+. Binding of NAD+ inhibited the interaction of DBC1 with PARP1 [poly(adenosine diphosphate–ribose) polymerase 1], an enzyme important in DNA repair. Activity of PARP1 is inhibited by interaction with DBC1. Thus, the reduced abundance of NAD+ associated with aging may decrease PARP1 activity by promoting the interaction of PARP1 with DBC1. This mechanism could help explain the reported rejuvenating actions of NAD+ supplementation in older animals. Science, this issue p. 1312 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.

[1]  Damian Szklarczyk,et al.  Version 4.0 of PaxDb: Protein abundance data, integrated across model organisms, tissues, and cell‐lines , 2015, Proteomics.

[2]  M. Ziegler,et al.  Subcellular Compartmentation and Differential Catalytic Properties of the Three Human Nicotinamide Mononucleotide Adenylyltransferase Isoforms* , 2005, Journal of Biological Chemistry.

[3]  Michael Levitt,et al.  KoBaMIN: a knowledge-based minimization web server for protein structure refinement , 2012, Nucleic Acids Res..

[4]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[5]  K. S. Bhullar,et al.  Lifespan and healthspan extension by resveratrol. , 2015, Biochimica et biophysica acta.

[6]  S. Gygi,et al.  A High-Confidence Interaction Map Identifies SIRT1 as a Mediator of Acetylation of USP22 and the SAGA Coactivator Complex , 2013, Molecular and Cellular Biology.

[7]  M. Massiah,et al.  Structures and mechanisms of Nudix hydrolases. , 2005, Archives of biochemistry and biophysics.

[8]  Max Hasmann,et al.  FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. , 2003, Cancer research.

[9]  P. A. Loeffler,et al.  Structural studies of the PARP-1 BRCT domain , 2011, BMC Structural Biology.

[10]  T. Walsh,et al.  DBC2, a candidate for a tumor suppressor gene involved in breast cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Peer Bork,et al.  A superfamily of conserved domains in DNA damage‐ responsive cell cycle checkpoint proteins , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  L. Guarente,et al.  The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling , 2013, Cell.

[13]  A. Tutt,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial , 2010, The Lancet.

[14]  Johannes Söding,et al.  The HHpred interactive server for protein homology detection and structure prediction , 2005, Nucleic Acids Res..

[15]  L. Aravind,et al.  Analysis of DBC1 and its homologs suggests a potential mechanism for regulation of Sirtuin domain deacetylases by NAD metabolites , 2008, Cell cycle.

[16]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[17]  D. Cozzetto,et al.  Relationship between multiple sequence alignments and quality of protein comparative models , 2004, Proteins.

[18]  Dudley Lamming,et al.  Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival , 2007, Cell.

[19]  S. Imai,et al.  The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells* , 2004, Journal of Biological Chemistry.

[20]  L. Christophorou.  Science , 2018, Emerging Dynamics: Science, Energy, Society and Values.

[21]  Thomas L. Madden,et al.  Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. , 1997, Nucleic acids research.

[22]  Junjie Chen,et al.  DBC1 is a negative regulator of SIRT1 , 2008, Nature.

[23]  D. Sinclair,et al.  Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds , 2016, Nature Reviews Molecular Cell Biology.

[24]  L. Guarente,et al.  NAD+ and sirtuins in aging and disease. , 2014, Trends in cell biology.

[25]  D. Sinclair,et al.  Mammalian sirtuins: biological insights and disease relevance. , 2010, Annual review of pathology.

[26]  Dudley Lamming,et al.  Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators , 2013, Science.

[27]  R. Rosenfeld.  Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[28]  Geoffrey J. Barton,et al.  JPred : a consensus secondary structure prediction server , 1999 .

[29]  B. Garcia,et al.  Proteomics , 2011, Journal of biomedicine & biotechnology.

[30]  W. Kraus,et al.  PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. , 2010, Molecular cell.

[31]  A. Seluanov,et al.  SIRT6 Promotes DNA Repair Under Stress by Activating PARP1 , 2011, Science.

[32]  W. Kraus,et al.  The DNA Binding and Catalytic Domains of Poly(ADP-Ribose) Polymerase 1 Cooperate in the Regulation of Chromatin Structure and Transcription , 2007, Molecular and Cellular Biology.

[33]  A. Bürkle,et al.  Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[34]  A. Seluanov,et al.  Changes in DNA repair during aging , 2007, Nucleic acids research.

[35]  A. Seluanov,et al.  DNA repair by homologous recombination, but not by nonhomologous end joining, is elevated in breast cancer cells. , 2009, Neoplasia.

[36]  Guy G. Poirier,et al.  Proteome-wide identification of poly(ADP-ribose) binding proteins and poly(ADP-ribose)-associated protein complexes , 2008, Nucleic acids research.

[37]  A. Caflisch,et al.  Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases , 2013, Nature Structural &Molecular Biology.

[38]  Bill Bynum,et al.  Lancet , 2015, The Lancet.

[39]  S. Imai,et al.  Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. , 2011, Cell metabolism.

[40]  E. Mercken,et al.  Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging , 2013, Cell.

[41]  V. Hu.  The Cell Cycle , 1994, GWUMC Department of Biochemistry Annual Spring Symposia.

[42]  Jie Yao,et al.  Regulation of Poly(ADP-ribose) Polymerase-1-dependent Gene Expression through Promoter-directed Recruitment of a Nuclear NAD+ Synthase* , 2012, The Journal of Biological Chemistry.

[43]  Jimin Pei,et al.  PROMALS: towards accurate multiple sequence alignments of distantly related proteins , 2007, Bioinform..

[44]  J. Auwerx,et al.  The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. , 2010, Endocrine reviews.

[45]  Erik L. L. Sonnhammer,et al.  Kalign – an accurate and fast multiple sequence alignment algorithm , 2005, BMC Bioinformatics.

[46]  Frederick W. Alt,et al.  DNA Repair, Genome Stability, and Aging , 2005, Cell.