* 607033

TRANSCRIPTION FACTOR B1, MITOCHONDRIAL; TFB1M


Alternative titles; symbols

MITOCHONDRIAL 12S rRNA DIMETHYLASE 1
DIMETHYLADENOSINE TRANSFERASE 1, MITOCHONDRIAL
CGI75
mtTFB1


HGNC Approved Gene Symbol: TFB1M

Cytogenetic location: 6q25.3     Genomic coordinates (GRCh38): 6:155,229,871-155,314,484 (from NCBI)


TEXT

Description

The transcription of genes from mitochondrial DNA requires a mitochondrial RNA polymerase (see POLRMT, 601778) and a DNA-binding transcription factor (see TFAM, 600438). Transcription factor B1 (TFB1M) is a part of this transcription complex (McCulloch et al., 2002).


Cloning and Expression

By database searching for sequences showing homology to S. cerevisiae and S. pombe TFB proteins, McCulloch et al. (2002) identified human TFB1M, which they designated CGI-75, and assembled the complete sequence from available ESTs. The deduced 346-amino acid protein shares 16% identity with the S. pombe homolog. Upon transfection into HeLa cells, fluorescence-labeled TFB1M colocalized with mitochondrial markers in a punctate cytoplasmic staining pattern.


Gene Structure

By sequence analysis of the genomic DNA directly upstream from TFB1M, McCulloch et al. (2002) identified putative binding sites for several nuclear transcription factors, including 2 sites for nuclear respiratory factor-2 (600609), which activates the transcription of several nuclear-encoded mitochondrial proteins.


Mapping

During manual annotation of chromosome 6, Mungall et al. (2003) identified the TFB1M gene at chromosome 6q25.2-q25.3.


Gene Function

By gel mobility shift assay, McCulloch et al. (2002) found that recombinant TFB1M binds to the mitochondrial light strand promoter (LSP). With addition of a nonspecific competitor to the reaction, they determined that the binding is largely independent of the DNA sequence. They further found that TFB1M significantly enhanced transcription from LSP by TFAM in an in vitro mitochondrial transcription reaction, but was itself transcriptionally inactive. McCulloch et al. (2002) noted sequence similarity between TFB1M and several rRNA adenine dimethyltransferase enzymes and verified by solid-phase in vitro binding assays that recombinant TFB1M could bind S-adenosylmethionine.

Seidel-Rogol et al. (2003) showed that TFB1M appears to be a dual-function protein, acting both as a transcription factor and as an rRNA modification enzyme. The data showed that the protein methylates a conserved stem-loop in bacterial 16S rRNA and that the homologous sequence in the human mitochondrial 12S molecule is similarly modified.

Cotney et al. (2009) demonstrated that TFB1M and TFB2M (607055) are key downstream effectors of mitochondrial biogenesis that perform unique, yet cooperative functions. The primary function of TFB2M is mtDNA transcription and maintenance, which is independent of its rRNA methyltransferase activity, while that of TFB1M is mitochondrial 12S rRNA (561000) methylation needed for normal mitochondrial translation, metabolism, and cell growth. Overexpression of TFB1M caused 12S rRNA hypermethylation, aberrant mitochondrial biogenesis, and increased sorbitol-induced cell death. These phenotypes were recapitulated in cells harboring the pathogenic 1555A-G mtDNA mutation (561000.0001), implicating a deleterious rRNA methylation-dependent retrograde signal in maternally inherited deafness (221745) pathology.


Biochemical Features

Itoh et al. (2022) determined sequential cryoelectron microscopy structures of stable assembly intermediates and initiation complexes of human mitoribosomes at 2.8- to 3.2-angstrom resolution that involved 6 factors: RBFA (620768), TFB1M, METTL15 (618711), MTIF3 (619554), MS37 (CHCHD1; 608842), and MTIF2 (603766). The earliest intermediate small mitoribosomal subunit (SSU) contained RBFA and TFB1M and partially unfolded rRNA. RBFA promoted TFB1M binding to partially unfolded rRNA, while the mRNA channel was blocked. This conformation enabled binding of METTL15, which promoted further rRNA maturation and a large conformational change of RBFA. The new RBFA conformation allowed initiation factor MTIF3 to occupy the subunit interface during assembly. Finally, the mitochondria-specific ribosomal protein MS37 outcompeted RBFA to release it and complete assembly with the SSU-MS37-MTIF3 complex that proceeded towards MTIF2 binding and translation initiation.


Animal Model

TFB1M dimethylates the N6 position of 2 adjacent adenosines within the loop of helix 45 at the 3-prime end of 12S rRNA. Lee et al. (2015) found that transgenic overexpression of Tfb1m in mice had no apparent effects, including on hearing. The 2 adenosines in rRNA were over 97% dimethylated in liver and heart of both wildtype and Tfb1m-overexpressing mice. Homozygous Tfb1m knockout in heart reduced 12S rRNA methylation to below 40% and caused progressive cardiomyopathy.


REFERENCES

  1. Cotney, J., McKay, S. E., Shadel, G. S. Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness. Hum. Molec. Genet. 18: 2670-2682, 2009. [PubMed: 19417006, images, related citations] [Full Text]

  2. Itoh, Y., Khawaja, A., Laptev, I., Cipullo, M., Atanassov, I., Sergiev, P., Rorbach, J., Amunts, A. Mechanism of mitoribosomal small subunit biogenesis and preinitiation. Nature 606: 603-608, 2022. [PubMed: 35676484, images, related citations] [Full Text]

  3. Lee, S., Rose, S., Metodiev, M. D., Becker, L., Vernaleken, A., Klopstock, T., Gailus-Durner, V., Fuchs, H., De Angelis, M. H., Douthwaite, S., Larsson, N.-G. Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status or hearing. Hum. Molec. Genet. 24: 7286-7294, 2015. [PubMed: 26464487, images, related citations] [Full Text]

  4. McCulloch, V., Seidel-Rogol, B. L., Shadel, G. S. A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine. Molec. Cell. Biol. 22: 1116-1125, 2002. [PubMed: 11809803, images, related citations] [Full Text]

  5. Mungall, A. J., Palmer, S. A., Sims, S. K., Edwards, C. A., Ashurst, J. L., Wilming, L., Jones, M. C., Horton, R., Hunt, S. E., Scott, C. E., Gilbert, J. G. R., Clamp, M. E., and 158 others. The DNA sequence and analysis of human chromosome 6. Nature 425: 805-811, 2003. [PubMed: 14574404, related citations] [Full Text]

  6. Seidel-Rogol, B. L., McCulloch, V., Shadel, G. S. Human mitochondrial transcription factor B1 methylates ribosomal RNA at a conserved stem-loop. Nature Genet. 33: 23-24, 2003. [PubMed: 12496758, related citations] [Full Text]


Bao Lige - updated : 03/22/2024
Patricia A. Hartz - updated : 09/22/2016
George E. Tiller - updated : 4/1/2010
Victor A. McKusick - updated : 12/20/2002
Creation Date:
Patricia A. Hartz : 6/12/2002
mgross : 03/22/2024
mgross : 09/22/2016
wwang : 04/15/2010
terry : 4/1/2010
alopez : 12/23/2002
terry : 12/20/2002
carol : 6/13/2002
carol : 6/12/2002

* 607033

TRANSCRIPTION FACTOR B1, MITOCHONDRIAL; TFB1M


Alternative titles; symbols

MITOCHONDRIAL 12S rRNA DIMETHYLASE 1
DIMETHYLADENOSINE TRANSFERASE 1, MITOCHONDRIAL
CGI75
mtTFB1


HGNC Approved Gene Symbol: TFB1M

Cytogenetic location: 6q25.3     Genomic coordinates (GRCh38): 6:155,229,871-155,314,484 (from NCBI)


TEXT

Description

The transcription of genes from mitochondrial DNA requires a mitochondrial RNA polymerase (see POLRMT, 601778) and a DNA-binding transcription factor (see TFAM, 600438). Transcription factor B1 (TFB1M) is a part of this transcription complex (McCulloch et al., 2002).


Cloning and Expression

By database searching for sequences showing homology to S. cerevisiae and S. pombe TFB proteins, McCulloch et al. (2002) identified human TFB1M, which they designated CGI-75, and assembled the complete sequence from available ESTs. The deduced 346-amino acid protein shares 16% identity with the S. pombe homolog. Upon transfection into HeLa cells, fluorescence-labeled TFB1M colocalized with mitochondrial markers in a punctate cytoplasmic staining pattern.


Gene Structure

By sequence analysis of the genomic DNA directly upstream from TFB1M, McCulloch et al. (2002) identified putative binding sites for several nuclear transcription factors, including 2 sites for nuclear respiratory factor-2 (600609), which activates the transcription of several nuclear-encoded mitochondrial proteins.


Mapping

During manual annotation of chromosome 6, Mungall et al. (2003) identified the TFB1M gene at chromosome 6q25.2-q25.3.


Gene Function

By gel mobility shift assay, McCulloch et al. (2002) found that recombinant TFB1M binds to the mitochondrial light strand promoter (LSP). With addition of a nonspecific competitor to the reaction, they determined that the binding is largely independent of the DNA sequence. They further found that TFB1M significantly enhanced transcription from LSP by TFAM in an in vitro mitochondrial transcription reaction, but was itself transcriptionally inactive. McCulloch et al. (2002) noted sequence similarity between TFB1M and several rRNA adenine dimethyltransferase enzymes and verified by solid-phase in vitro binding assays that recombinant TFB1M could bind S-adenosylmethionine.

Seidel-Rogol et al. (2003) showed that TFB1M appears to be a dual-function protein, acting both as a transcription factor and as an rRNA modification enzyme. The data showed that the protein methylates a conserved stem-loop in bacterial 16S rRNA and that the homologous sequence in the human mitochondrial 12S molecule is similarly modified.

Cotney et al. (2009) demonstrated that TFB1M and TFB2M (607055) are key downstream effectors of mitochondrial biogenesis that perform unique, yet cooperative functions. The primary function of TFB2M is mtDNA transcription and maintenance, which is independent of its rRNA methyltransferase activity, while that of TFB1M is mitochondrial 12S rRNA (561000) methylation needed for normal mitochondrial translation, metabolism, and cell growth. Overexpression of TFB1M caused 12S rRNA hypermethylation, aberrant mitochondrial biogenesis, and increased sorbitol-induced cell death. These phenotypes were recapitulated in cells harboring the pathogenic 1555A-G mtDNA mutation (561000.0001), implicating a deleterious rRNA methylation-dependent retrograde signal in maternally inherited deafness (221745) pathology.


Biochemical Features

Itoh et al. (2022) determined sequential cryoelectron microscopy structures of stable assembly intermediates and initiation complexes of human mitoribosomes at 2.8- to 3.2-angstrom resolution that involved 6 factors: RBFA (620768), TFB1M, METTL15 (618711), MTIF3 (619554), MS37 (CHCHD1; 608842), and MTIF2 (603766). The earliest intermediate small mitoribosomal subunit (SSU) contained RBFA and TFB1M and partially unfolded rRNA. RBFA promoted TFB1M binding to partially unfolded rRNA, while the mRNA channel was blocked. This conformation enabled binding of METTL15, which promoted further rRNA maturation and a large conformational change of RBFA. The new RBFA conformation allowed initiation factor MTIF3 to occupy the subunit interface during assembly. Finally, the mitochondria-specific ribosomal protein MS37 outcompeted RBFA to release it and complete assembly with the SSU-MS37-MTIF3 complex that proceeded towards MTIF2 binding and translation initiation.


Animal Model

TFB1M dimethylates the N6 position of 2 adjacent adenosines within the loop of helix 45 at the 3-prime end of 12S rRNA. Lee et al. (2015) found that transgenic overexpression of Tfb1m in mice had no apparent effects, including on hearing. The 2 adenosines in rRNA were over 97% dimethylated in liver and heart of both wildtype and Tfb1m-overexpressing mice. Homozygous Tfb1m knockout in heart reduced 12S rRNA methylation to below 40% and caused progressive cardiomyopathy.


REFERENCES

  1. Cotney, J., McKay, S. E., Shadel, G. S. Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness. Hum. Molec. Genet. 18: 2670-2682, 2009. [PubMed: 19417006] [Full Text: https://doi.org/10.1093/hmg/ddp208]

  2. Itoh, Y., Khawaja, A., Laptev, I., Cipullo, M., Atanassov, I., Sergiev, P., Rorbach, J., Amunts, A. Mechanism of mitoribosomal small subunit biogenesis and preinitiation. Nature 606: 603-608, 2022. [PubMed: 35676484] [Full Text: https://doi.org/10.1038/s41586-022-04795-x]

  3. Lee, S., Rose, S., Metodiev, M. D., Becker, L., Vernaleken, A., Klopstock, T., Gailus-Durner, V., Fuchs, H., De Angelis, M. H., Douthwaite, S., Larsson, N.-G. Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status or hearing. Hum. Molec. Genet. 24: 7286-7294, 2015. [PubMed: 26464487] [Full Text: https://doi.org/10.1093/hmg/ddv427]

  4. McCulloch, V., Seidel-Rogol, B. L., Shadel, G. S. A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine. Molec. Cell. Biol. 22: 1116-1125, 2002. [PubMed: 11809803] [Full Text: https://doi.org/10.1128/MCB.22.4.1116-1125.2002]

  5. Mungall, A. J., Palmer, S. A., Sims, S. K., Edwards, C. A., Ashurst, J. L., Wilming, L., Jones, M. C., Horton, R., Hunt, S. E., Scott, C. E., Gilbert, J. G. R., Clamp, M. E., and 158 others. The DNA sequence and analysis of human chromosome 6. Nature 425: 805-811, 2003. [PubMed: 14574404] [Full Text: https://doi.org/10.1038/nature02055]

  6. Seidel-Rogol, B. L., McCulloch, V., Shadel, G. S. Human mitochondrial transcription factor B1 methylates ribosomal RNA at a conserved stem-loop. Nature Genet. 33: 23-24, 2003. [PubMed: 12496758] [Full Text: https://doi.org/10.1038/ng1064]


Contributors:
Bao Lige - updated : 03/22/2024
Patricia A. Hartz - updated : 09/22/2016
George E. Tiller - updated : 4/1/2010
Victor A. McKusick - updated : 12/20/2002

Creation Date:
Patricia A. Hartz : 6/12/2002

Edit History:
mgross : 03/22/2024
mgross : 09/22/2016
wwang : 04/15/2010
terry : 4/1/2010
alopez : 12/23/2002
terry : 12/20/2002
carol : 6/13/2002
carol : 6/12/2002