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- W2022157823 abstract "Expression of mtDNA is critical for biogenesis of the oxidative phosphorylation system, but the regulatory processes are poorly understood. Recent work in Cell (Yakubovskaya et al., 2010Yakubovskaya E. Mejia E. Byrnes J. Hambardjieva E. Garcia-Diaz M. Cell. 2010; 141: 982-993Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar) reports a novel DNA-binding fold in mitochondrial transcription termination factor 1 (MTERF1), which causes unwinding and base eversion at its target mtDNA sequence. Expression of mtDNA is critical for biogenesis of the oxidative phosphorylation system, but the regulatory processes are poorly understood. Recent work in Cell (Yakubovskaya et al., 2010Yakubovskaya E. Mejia E. Byrnes J. Hambardjieva E. Garcia-Diaz M. Cell. 2010; 141: 982-993Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar) reports a novel DNA-binding fold in mitochondrial transcription termination factor 1 (MTERF1), which causes unwinding and base eversion at its target mtDNA sequence. Mitochondrial dysfunction is an important cause of human disease and is heavily implicated in age-associated diseases and aging (Larsson, 2010Larsson N.G. Annu. Rev. Biochem. 2010; 79: 683-706Crossref PubMed Scopus (330) Google Scholar). Regulation of mtDNA expression is essential for maintaining cellular energy homeostasis because biogenesis of the oxidative phosphorylation system is critically dependent on key subunits encoded by mtDNA. For more than two decades, MTERF1 has been implicated in regulating transcription termination in mammalian mitochondria, but its molecular mode of action has remained elusive. In a recent breakthrough study published in Cell, the atomic structure of MTERF1-bound mtDNA was solved (Yakubovskaya et al., 2010Yakubovskaya E. Mejia E. Byrnes J. Hambardjieva E. Garcia-Diaz M. Cell. 2010; 141: 982-993Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Of interest, the MTERF1 protein has a novel fold, unwinds its DNA target, and causes base eversion (Figure 1A ), which is critical for transcription termination (Yakubovskaya et al., 2010Yakubovskaya E. Mejia E. Byrnes J. Hambardjieva E. Garcia-Diaz M. Cell. 2010; 141: 982-993Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Transcription of mammalian mtDNA occurs from a dedicated promoter on each strand, and the long primary transcripts undergo processing to release 13 mRNAs, 2 rRNAs, and 22 tRNAs (Larsson, 2010Larsson N.G. Annu. Rev. Biochem. 2010; 79: 683-706Crossref PubMed Scopus (330) Google Scholar). Initiation of transcription at the heavy-strand promoter (HSP) produces the mitochondrial rRNAs as well as several downstream mRNAs and tRNAs. In the early 1980s, data from pulse-chase labeling of mitochondrial RNAs in mammalian cell lines provided support for a model whereby the rRNA genes constitute a separate transcription unit. Other studies showed that a tridecamer sequence in the tRNAL1 gene, located immediately downstream of the rRNA genes, could promote transcription termination in vitro. The factor binding this sequence was denoted MTERF1 and was further characterized by purification and cloning (Fernandez-Silva et al., 1997Fernandez-Silva P. Martinez-Azorin F. Micol V. Attardi G. EMBO J. 1997; 16: 1066-1079Crossref PubMed Scopus (136) Google Scholar). This new study presents the crystal structure of MTERF1 bound to its target sequence in the tRNAL1 gene at a resolution of 2.2 Å (Yakubovskaya et al., 2010Yakubovskaya E. Mejia E. Byrnes J. Hambardjieva E. Garcia-Diaz M. Cell. 2010; 141: 982-993Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Previous predictions had suggested that intramolecular leucine zippers were an important feature determining MTERF3 structure (Fernandez-Silva et al., 1997Fernandez-Silva P. Martinez-Azorin F. Micol V. Attardi G. EMBO J. 1997; 16: 1066-1079Crossref PubMed Scopus (136) Google Scholar). Unexpectedly, the new study shows that MTERF1 instead has a novel DNA-binding fold and an essentially modular architecture consisting of eight repeated mterf motifs (Figure 1A). Each mterf motif contains two α helices followed by a 310 helix that together form a tilted triangle. Hydrophic interactions between neighboring motifs stabilize the protein, and the overall structure adopts a curved shape resembling half of a doughnut (Figure 1A). MTERF1 binds mtDNA as a monomer but has an unusually long footprint on the DNA and covers 20 base pairs. The binding of MTERF1 leads to partial melting of the DNA duplex with eversion of three nucleotides. These flipped DNA bases are stabilized by hydrogen bonds and stacking interactions with amino acids in the MTERF1 protein. The observed base flipping is essential for effective transcription termination but is not required for binding and bending of mtDNA. The interactions with DNA are, in fact, primarily electrostatic in nature, as the negatively charged DNA backbone interacts with positively charged grooves on the protein surface. The structural data explain why MTERF1 interacts with its preferred binding site in the tRNAL1 gene and also provide an explanation for the experimentally observed unspecific DNA-binding activity (Park et al., 2007Park C.B. Asin-Cayuela J. Cámara Y. Shi Y. Pellegrini M. Gaspari M. Wibom R. Hultenby K. Erdjument-Bromage H. Tempst P. et al.Cell. 2007; 130: 273-285Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, Yakubovskaya et al., 2010Yakubovskaya E. Mejia E. Byrnes J. Hambardjieva E. Garcia-Diaz M. Cell. 2010; 141: 982-993Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). The novel structure is a very important step toward a molecular understanding of MTERF1, but there is, in fact, still no in vivo evidence showing that it regulates mitochondrial transcription termination. On the contrary, molecular characterization of patients with the A3243G mutation in the tRNAL1 gene, exhibiting mitochondrial myopathy, encephalopathy, lactic-acidosis, and stroke-like episodes syndrome (MELAS), provides no support for defective mitochondrial transcription termination but instead argues that impaired mitochondrial translation due to defective function of the mutant tRNAL1 is of central pathophysiological importance (Chomyn et al., 1992Chomyn A. Martinuzzi A. Yoneda M. Daga A. Hurko O. Johns D. Lai S.T. Nonaka I. Angelini C. Attardi G. Proc. Natl. Acad. Sci. USA. 1992; 89: 4221-4225Crossref PubMed Scopus (431) Google Scholar). This finding is surprising, as the causative A3243G mutation in MELAS patients destroys the MTERF1-binding site in the tRNAL1 gene and strongly impairs transcription termination in vitro (Chomyn et al., 1992Chomyn A. Martinuzzi A. Yoneda M. Daga A. Hurko O. Johns D. Lai S.T. Nonaka I. Angelini C. Attardi G. Proc. Natl. Acad. Sci. USA. 1992; 89: 4221-4225Crossref PubMed Scopus (431) Google Scholar). It cannot be excluded that the normally occurring difference in relative abundance of rRNAs and mRNAs is mainly explained by different stabilities. If so, termination of transcription initiated from HSP may have no role in regulating rRNA levels, and MTERF1 may instead have another function in transcription or perhaps even regulate mtDNA replication. It is a very important aim for the future to define the in vivo role of MTERF1 by creating mouse knockouts in which both copies of the repeated Mterf1 gene are inactivated. It has been reported that MTERF1 interacts with both the binding site in the tRNAL1 gene and with HSP to form an mtDNA loop containing the rRNA transcription unit (Martin et al., 2005Martin M. Cho J. Cesare A.J. Griffith J.D. Attardi G. Cell. 2005; 123: 1227-1240Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). The concept of a separate transcription unit for the rRNA genes has recently been questioned, as another study did not detect binding of MTERF1 to HSP (Park et al., 2007Park C.B. Asin-Cayuela J. Cámara Y. Shi Y. Pellegrini M. Gaspari M. Wibom R. Hultenby K. Erdjument-Bromage H. Tempst P. et al.Cell. 2007; 130: 273-285Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar), and in vitro transcription studies have not supported the existence of a second HSP (Litonin et al., 2010Litonin D. Sologub M. Shi Y. Savkina M. Anikin M. Falkenberg M. Gustafsson C.M. Temiakov D. J. Biol. Chem. 2010; 285: 18129-18133Crossref PubMed Scopus (127) Google Scholar). The new structural data show that MTERF1 binds mtDNA as a monomer, and protein dimerization is therefore unlikely to explain the proposed loop formation. The original model also suggested that MTERF1 terminates transcription initiated from HSP; however, termination in this direction is far less efficient than termination of in vitro transcription from the opposite direction (Asin-Cayuela et al., 2005Asin-Cayuela J. Schwend T. Farge G. Gustafsson C.M. J. Biol. Chem. 2005; 280: 25499-25505Crossref PubMed Scopus (48) Google Scholar). The new structure shows that MTERF1 primarily interacts with one of the two DNA strands, which may explain the directional effect on transcription termination. This observation also raises the question of whether MTERF1 actually functions to terminate transcription initiated from light-strand promoter (LSP) to avoid formation of RNAs that are antisense to the rRNAs. There is a family of four MTERF1-related factors in mammalian mitochondria, and at least two of these, MTERF2 and MTERF3, are implicated in transcription regulation, whereas the function of MTERF4 remains to be characterized. The MTERF3 protein binds the promoter region of mtDNA, and immunodepletion of MTERF3 in mitochondrial extracts leads to activation of mitochondrial transcription (Park et al., 2007Park C.B. Asin-Cayuela J. Cámara Y. Shi Y. Pellegrini M. Gaspari M. Wibom R. Hultenby K. Erdjument-Bromage H. Tempst P. et al.Cell. 2007; 130: 273-285Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Germ-line ablation of the Mterf3 gene causes embryonic lethality, and conditional knockout of Mterf3 in the heart leads to a massive activation of mtDNA transcription consistent with a role in repressing mtDNA transcription (Park et al., 2007Park C.B. Asin-Cayuela J. Cámara Y. Shi Y. Pellegrini M. Gaspari M. Wibom R. Hultenby K. Erdjument-Bromage H. Tempst P. et al.Cell. 2007; 130: 273-285Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Mice lacking Mterf2 are viable but develop an imbalance in mitochondrial transcript levels when challenged by a ketogenic diet (Wenz et al., 2009Wenz T. Luca C. Torraco A. Moraes C.T. Cell Metab. 2009; 9: 499-511Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). A recent partial structure of MTERF3 (Spåhr et al., 2010Spåhr H. Samuelsson T. Hällberg B.M. Gustafsson C.M. Biochem. Biophys. Res. Commun. 2010; (in press. 10.1016/j.bbrc.2010.04.130)PubMed Google Scholar) (Figure 1B) shows a striking similarity to the published MTERF1 structure; both have almost identical half-doughnut shapes consisting of mterf motif repeats (Figure 1C). However, there are also important differences, as only one of the five arginines necessary for sequence-specific DNA binding and only one of the three amino acids that stabilize base flipping are present in MTERF3 (Spåhr et al., 2010Spåhr H. Samuelsson T. Hällberg B.M. Gustafsson C.M. Biochem. Biophys. Res. Commun. 2010; (in press. 10.1016/j.bbrc.2010.04.130)PubMed Google Scholar). The structural data from MTERF1 and MTERF3 (Figures 1A–1C), however, suggest that all members of the MTERF family have similar folds and bind nucleic acids. Further characterization of the MTERF family members will likely lead to novel and exciting insights into how they regulate mammalian mtDNA gene expression." @default.
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- W2022157823 title "MTERF1 Gives mtDNA an Unusual Twist" @default.
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