Analysis of DBC1 and its homologs suggests a potential mechanism for regulation of sirtuin domain deacetylases by NAD metabolites.
Deleted in Breast Cancer-1 (DBC1) and its paralog CARP-1 are large multi-domain proteins, with a nuclear or perinuclear localization, and a role in promoting apoptosis upon processing by caspases. Recent studies on human DBC1 show that it is a specific inhibitor of the sirtuin-type deacetylase, Sirt1, which deacetylates histones and p53. Using sensitive sequence profile searches and HMM-HMM comparisons we show that the central conserved globular domain present in the DBC1 and it homologs from diverse eukaryotes is a catalytically inactive version of the Nudix hydrolase (MutT) domain. Given that Nudix domains are known to bind nucleoside diphosphate sugars and NAD, we predict that this domain in DBC1 and its homologs binds NAD metabolites such as ADP-ribose. Hence, we propose that DBC1 and its homologs are likely to regulate the activity of SIRT1 or related deacetylases by sensing the soluble products or substrates of the NAD-dependent deacetylation reaction. The complex domain architectures of the members of the DBC1 family, which include fusions to the RNA-binding S1-like domain, the DNA-binding SAP domain and EF-hand domains, suggest that they are likely to function as integrators of distinct regulatory signals including chromatin protein modification, soluble compounds in NAD metabolism, apoptotic stimuli and RNA recognition.
Anantharaman
Vivek
V
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
Aravind
L
L
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D018797:Cell Cycle Proteins; D019295:Computational Biology; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D017434:Protein Structure, Tertiary; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
C112308:BRINP1 protein, human; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D000246:Adenosine Diphosphate Ribose; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins