Alternative titles; symbols
HGNC Approved Gene Symbol: MTERF1
Cytogenetic location: 7q21.2 Genomic coordinates (GRCh38): 7:91,870,929-91,880,702 (from NCBI)
Mitochondrial transcription termination factor (MTERF) plays a central role in attenuating transcription between the 16S ribosomal RNA (561010) and the tRNA-leu (590050) genes in the heavy strand of mitochondrial DNA. By doing so, MTERF is part of the regulatory system that allows high levels of ribosomal RNA expression relative to downstream genes (summary by Daga et al. (1993) and Fernandez-Silva et al. (1997)).
From HeLa cells, Daga et al. (1993) purified 2 related 34-kD polypeptides that had MTERF activity. Fernandez-Silva et al. (1997) cloned the MTERF cDNA by RT-PCR of HeLa cell mRNA using primers derived from peptide sequences of the purified protein. The cDNA encoded a predicted 399-amino acid protein containing a mitochondrial targeting sequence. The mature MTERF protein is 342 amino acids long and contains 3 leucine zipper and 2 basic domains.
By mutational analysis, Fernandez-Silva et al. (1997) showed that all of the leucine zipper and basic domains of MTERF were necessary for DNA binding. The 2 basic domains were involved in directly binding MTERF to its target DNA sequence. MTERF bound DNA as a monomer.
Using gel filtration and PCR for repeated selection of bound sequences from a random pool of double-stranded DNA, Nam and Kang (2005) found that MTERF bound a 16-bp consensus sequence containing the 13-bp termination sequence within tRNA-leu(UUR). MTERF bound single-stranded DNA containing this sequence from the mitochondrial light strand, but not the heavy strand. Nam and Kang (2005) hypothesized that preferential binding of MTERF to the light strand may explain its orientation-dependent termination activity.
Yakubovskaya et al. (2010) determined the 2.2-angstrom crystal structure of mature human MTERF1 bound to double-stranded DNA (nucleotides 3232 to 3253 of mitochondrial DNA) containing the termination sequence within leu-tRNA(UUR). MTERF1 folded into 8 motifs, termed MTERF motifs, consisting of 2 alpha helices followed by a 3(10) helix. MTERF1 showed relative rigidity within individual motifs, but flexibility between them. MTERF1 bound along the major groove of DNA, slightly bending the DNA to 25 degrees. Most interactions were established with phosphate groups of the DNA, and sequence specificity was determined by hydrogen bonding between 5 arginines of MTERF1 and guanine bases of the termination sequence. MTERF1 binding unwound the DNA molecule and promoted partial duplex melting. Binding also caused eversion of 3 nucleotides, which were stabilized by a stacking interaction. Mutation of any of the 5 critical arginines in MTERF1 interfered with transcriptional termination in a transcription run-off assay. Base flipping was also critical for transcriptional termination. Mutations within the transcriptional termination sequence of leu-tRNA(UUR), which cause MELAS syndrome (540000), interfered with MTERF1 binding and transcriptional termination.
Gross (2013) mapped the MTERF1 gene to chromosome 7q21.2 based on an alignment of the MTERF1 sequence (GenBank BC000965) with the genomic sequence (GRCh37).
Daga, A., Micol, V., Hess, D., Aebersold, R., Attardi, G. Molecular characterization of the transcription termination factor from human mitochondria. J. Biol. Chem. 268: 8123-8130, 1993. [PubMed: 7681833]
Fernandez-Silva, P., Martinez-Azorin, F., Micol, V., Attardi, G. The human mitochondrial transcription termination factor (mTERF) is a multizipper protein but binds to DNA as a monomer, with evidence pointing to intramolecular leucine zipper interactions. EMBO J. 16: 1066-1079, 1997. [PubMed: 9118945] [Full Text: https://doi.org/10.1093/emboj/16.5.1066]
Gross, M. B. Personal Communication. Baltimore, Md. 9/19/2013.
Nam, S.-C., Kang, C. DNA light-strand preferential recognition of human mitochondria transcription termination factor mTERF. J. Biochem. Molec. Biol. 38: 690-694, 2005. [PubMed: 16336784] [Full Text: https://doi.org/10.5483/bmbrep.2005.38.6.690]
Yakubovskaya, E., Mejia, E., Byrnes, J., Hambardjieva, E., Garcia-Diaz, M. Helix unwinding and base flipping enable human MTERF1 to terminate mitochondrial transcription. Cell 141: 982-993, 2010. [PubMed: 20550934] [Full Text: https://doi.org/10.1016/j.cell.2010.05.018]