Alternative titles; symbols
HGNC Approved Gene Symbol: TERF2IP
Cytogenetic location: 16q23.1 Genomic coordinates (GRCh38) : 16:75,647,773-75,657,432 (from NCBI)
By performing a yeast 2-hybrid screen on a HeLa cell cDNA library using telomeric repeat-binding factor-2, or TRF2 (TERF2; 602027), as bait, followed by screening a breast cancer cDNA library, Li et al. (2000) isolated a full-length cDNA encoding RAP1, an ortholog of the yeast telomeric protein Rap1. The RAP1 cDNA is identical to the KAIA804 cDNA (GenBank AK000669) reported by the NEDO Japanese sequencing project. The predicted 47-kD RAP1 protein contains 399 amino acids. A motif search revealed that RAP1 has an N-terminal BRCT domain and a central Myb-type helix-turn-helix motif. RAP1 also has an acidic C terminus (amino acids 214 to 382; pI around 3.8) featuring a predicted 33-amino acid coiled-coil region and a bipartite nuclear localization signal. Sequence alignments showed an additional region of sequence similarity in the C termini of yeast and human RAP1 that coincides with the main protein-protein interaction domain of S. cerevisiae Rap1. Thus, human RAP1 has 3 conserved sequence motifs in common with yeast Rap1. Northern blot analysis detected ubiquitous expression of a 2.5-kb RAP1 transcript. The authors found that RAP1 is localized to telomeres and affects telomere length. However, while yeast Rap1 binds telomeric DNA directly, human RAP1 is recruited to telomeres by TRF2. Extending the comparison of telomeric proteins to fission yeast, Li et al. (2000) identified the S. pombe Taz1 protein as a TRF ortholog, indicating that TRFs are conserved at eukaryotic telomeres. The data suggested that ancestral telomeres, like those of vertebrates, contained a TRF-like protein as well as RAP1. The authors proposed that budding yeast preserved Rap1 at telomeres but lost the TRF component, possibly concomitant with a change in the telomeric repeat sequence.
Lieb et al. (2001) determined the distribution of RAP1 in vivo on the entire yeast genome, at a resolution of 2 kb. RAP1 is central to the cellular economy during rapid growth, targeting 294 loci, about 5% of yeast genes, and participating in the activation of 37% of all RNA polymerase II (see 180660) initiation events in exponentially growing cells. Although the DNA sequence recognized by RAP1 is found in both coding and intergenic sequences, the binding of RAP1 to the genome was highly specific to intergenic regions with the potential to act as promoters. Lieb et al. (2001) concluded that this global phenomenon, which may be a general characteristic of sequence-specific transcriptional factors, indicates the existence of a genomewide molecular mechanism for marking promoter regions.
Sfeir et al. (2010) removed Rap1 from mouse telomeres either through gene deletion or by replacing Trf2 (602027) with a mutant that does not bind Rap1. Rap1 was dispensable for the essential functions of Trf2--repression of ATM kinase signaling and nonhomologous end-joining--and mice lacking telomeric Rap1 were viable and fertile. However, Rap1 was critical for the repression of homology-directed repair, which can alter telomere length. The data of Sfeir et al. (2010) revealed that homology-directed repair at telomeres can take place in the absence of DNA damage foci and underscore the functional compartmentalization within the shelterin complex.
Cryoelectron Microscopy
Papai et al. (2010) used cryoelectron microscopy to determine the architecture of nucleoprotein complexes composed of TFIID (313650), TFIIA (see 600519), the transcriptional activator RAP1, and yeast enhancer-promoter DNA. These structures revealed the mode of binding of RAP1 and TFIIA to TFIID, as well as a reorganization of TFIIA induced by its interaction with RAP1. Papai et al. (2010) proposed that this change in position increases the exposure of TATA box-binding protein within TFIID, consequently enhancing its ability to interact with the promoter. A large RAP1-dependent DNA loop forms between the activator-binding site and the proximal promoter region. This loop is topologically locked by a TFIIA-RAP1 protein bridge that folds over the DNA. These results highlighted the role of TFIIA in transcriptional activation, defined the molecular mechanism for enhancer-promoter communication, and provided structural insights into the pathways of intramolecular communication that convey transcription activation signals through the TFIID complex.
Li, B., Oestreich, S., de Lange, T. Identification of human Rap1: implications for telomere evolution. Cell 101: 471-483, 2000. [PubMed: 10850490] [Full Text: https://doi.org/10.1016/s0092-8674(00)80858-2]
Lieb, J. D., Liu, X., Botstein, D., Brown, P. O. Promoter-specific binding of Rap1 revealed by genome-wide maps of protein-DNA association. Nature Genet. 28: 327-334, 2001. Note: Erratum: Nature Genet. 29: 100 only, 2001. [PubMed: 11455386] [Full Text: https://doi.org/10.1038/ng569]
Papai, G., Tripathi, M. K., Ruhlmann, C., Layer, J. H., Weil, P. A., Schultz, P. TFIIA and the transactivator Rap1 cooperate to commit TFIID for transcription initiation. Nature 465: 956-960, 2010. [PubMed: 20559389] [Full Text: https://doi.org/10.1038/nature09080]
Sfeir, A., Kabir, S., van Overbeek, M., Celli, G. B., de Lange, T. Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal. Science 327: 1657-1661, 2010. [PubMed: 20339076] [Full Text: https://doi.org/10.1126/science.1185100]