Transcriptional regulation by C-terminal binding proteins.

C-terminal binding protein family members function predominantly as transcriptional corepressors in association with sequence specific DNA-binding transcriptional repressors. The vertebrates have two CtBP genes while the invertebrates contain a single gene. Genetic studies indicate that the CtBP genes play pivotal roles in animal development. The vertebrate C-terminal binding proteins (CtBP1 and CtBP2) are highly related and are functionally redundant for certain developmental processes and non-redundant for others. The animal C-terminal binding proteins exhibit structural and functional similarity to d-isomer-specific 2-hydroxy acid dehydrogenases (D2-HDH). They function as dimers, recruiting transcriptional regulators through two protein-binding interfaces in each monomer. The corepressor complex of CtBP1 contains enzymatic constituents that mediate coordinated histone modification by deacetylation and methylation of histone H3-Lysine 9 and demethylation of histone H3-Lysine 4. CtBP also recruits the small ubiquitin-related modifier (SUMO) conjugating E2 enzyme UBC9 and a SUMO E3 ligase (HPC2), suggesting that CtBP-mediated transcriptional regulation may also involve SUMOylation of transcription factors. In addition to gene-specific transcriptional repression, CtBP1 appears to antagonize the activity of the global transcriptional coactivators, p300/CBP. Genetic evidence also suggests that the fly CtBP (dCtBP) and the vertebrate CtBP2 might activate transcription in a context-dependent manner. The transcriptional regulatory activity of CtBP is modulated by the nuclear NADH/NAD+ ratio and hence appears to be influenced by the metabolic status of the cell. The nuclear dinucleotide ratio may differentially influence the repression activities of factors that recruit CtBP through PLDLS-like motifs and those through non-PLDLS-motifs.