Transcription Corepressor CtBP Is an NAD+-Regulated Dehydrogenase

Department of Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Molecular Cell (Impact Factor: 14.02). 11/2002; 10(4):857-69. DOI: 10.1016/S1097-2765(02)00650-0
Source: PubMed


Transcriptional repression is based on the selective actions of recruited corepressor complexes, including those with enzymatic activities. One well-characterized developmentally important corepressor is the C-terminal binding protein (CtBP). Although intriguingly related in sequence to D2 hydroxyacid dehydrogenases, the mechanism by which CtBP functions remains unclear. We report here biochemical and crystallographic studies which reveal that CtBP is a functional dehydrogenase. In addition, both a cofactor-dependent conformational change, with NAD(+) and NADH being equivalently effective, and the active site residues are linked to the binding of the PXDLS consensus recognition motif on repressors, such as E1A and RIP140. Together, our data suggest that CtBP is an NAD(+)-regulated component of critical complexes for specific repression events in cells.

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    • "Astrocyte calcium signals are regulated by NAD+/NADH redox state (Requardt et al., 2012; Wilhelm and Hirrlinger, 2012), and changes in intracellular NAD+ and NADH levels arising from lactate fluxes may affect their binding to transcription factors and influence gene expression (Nakamura et al., 2012). For example, the transcription co-repressor, C-terminal binding protein (CtBP), is a dehydrogenase that undergoes conformational change with binding of NAD+ and NADH; NADH has a much higher affinity for CtBP, allowing it to serve as a redox sensor that destabilizes interactions with CtBP and transcription factors (Kumar et al., 2002; Fjeld et al., 2003). Increased NADH levels are thought to underlie seizure-induced increased expression of brain-derived neurotrophic factor (BDNF) and its receptor TrkB (Garriga-Canut et al., 2006). "
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    • "The function of CtBP2 NTR is regulated by acetylation by p300 [6]. As inferred from their amino acid sequence homology and similarities in three dimensional structures [7, 8](Pilka, ES et al., MMDB IP:4438), CtBP1 and CtBP2 are functionally redundant in the regulation of gene expression during animal development. However, they also perform unique developmental functions. "
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    ABSTRACT: C-terminal binding protein (CtBP) family transcriptional corepressors include CtBP1 and CtBP2. While CtBP1 and CtBP2 share significant amino acid sequence homology, CtBP2 possesses a unique N-terminal domain that is modified by acetylation and contributes to exclusive nuclear localization. Although CtBP1 and CtBP2 are functionally redundant for certain activities during vertebrate development, they also perform unique functions. Previous studies have identified several CtBP1-interacting proteins that included other transcriptional corepressors, DNA-binding repressors and histone modifying enzymatic components such as the histone deacetylases and the histone demethylase LSD-1. Here, we carried out an unbiased proteomic analysis of CtBP2-associated proteins and discovered the association of several components of the CtBP1 proteome as well as novel interactions. The CtBP2 proteome contained components of the NuRD complex and the E2F family member E2F7. E2F7 interacted with the hydrophobic cleft region of CtBP1 and CtBP2 through a prototypical CtBP binding motif, PIDLS. E2F7 repressed E2F1 transcription, inhibited cell proliferation in a CtBP-dependent fashion. Our study identified CtBP as a corepressor of E2F7 and as a regulator of DNA damage response.
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    • "Journal of Biomedicine and Biotechnology on NADH levels, and in particular high NADH levels promote CtBP dimerization as well as its interaction with other transcriptional repressors such as HIC1 [44] [45] [46] [47]. Cellular redox changes sensed by CtBP alter the affinity of the CtBP for HIC1 leading to a reduction of CtBP recruitment to Sirt1 promoter and hence derepression of its gene expression [43]. "
    Dataset: Sirtuins

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