Mammalian members of the C-terminal binding protein family of transcriptional repressors are recruited to promoters through interactions with DNA-bound transcription factors that contain amino acid motifs of the form PXDLS. Although similarly able to interact with PXDLS-containing transcription factors, we have found that the sole C. elegans member of this protein family, CTBP-1, also contains intrinsic DNA binding capacity in the form of a THAP domain. We have identified additional THAP domain-containing CtBPs in the nematode, echinoderm and cephalochordate lineages. The distribution of these lineages within the animal kingdom suggests that the ancestral form of the animal CtBPs may have contained a THAP domain that was subsequently lost in the vertebrate lineage.
Since determining the structure of the THAP domain of CTBP-1 by nuclear magnetic resonance spectroscopy, we have used a variety of biophysical approaches to define the DNA contact surface of this domain and to assess the affinity of binding to an 11 bp consensus binding site derived from site selection experiments. Using the CisOrtho program1 we have identified promoters that contain putative CTBP-1-THAP binding sites, representing candidate CTBP-1 target genes. With reference to both our own and published2 microarray datasets comparing transcripts from wild type animals with those from
ctbp-1 mutants, and to expression pattern data, we have defined a sub-set of these as likely in vivo targets of CTBP-1-mediated repression.
Given the reported role of CTBP-1 in the regulation of lifespan and stress resistance2, and other investigations implicating CTBP-1 in aspects of neuronal development (D. Yucel, unpublished), our identification of CTBP-1 target genes will make an important contribution to understanding the function of this transcriptional regulator in a range of contexts.
1.Bigelow HR, Wenick AS, Wong A, Hobert O. 2004. BMC Bioinformatics 5: 27
2.Chen S, Whetstine JR, Ghosh S, Hanover JA, Gali RR, et al. 2009. Proc Natl Acad Sci U S A 106: 1496-501.