[Frontiers in Bioscience, Landmark, 22, 835-853, January 1, 2017]

Mitochondrial transcription in mammalian cells

Inna N. Shokolenko 1 , Mikhail F. Alexeyev 2

1University of South Alabama, Patt Capps Covey College of Allied Health Professions, Biomedical Sciences Department, 5721 USA Drive N, HAHN 4021, Mobile, AL 36688-0002, USA, 2University of South Alabama, Department of Physiology and Cell Biology, 5151 USA Dr.North, MSB2058, Mobile, AL 36688, USA

FIGURES
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Figure 1. The map of human mtDNA. The clockwise orientation is according to the revised Cambridge Reference Sequence (rCRS, GenBank NC_012920.1.). Thin red bent arrows designate mitochondrial promoters that transcribe either H-strand (HSP1 and HSP2) or L-strand (LSP). Thin black and blue circular arrows, LSP and HSP2 transcripts, respectively. Thin green arch arrow, HSP1 transcript. Brown arrows: MT-ND1,-2,-3,-4,-5,-6, NADH dehydrogenase subunits 1 through 6. Purple arrows: MT-RNR1 and MT-RNR2, 12S and 16S rRNA genes. Blue arrows: MT-CO1-MT-CO3, cytochrome oxidase subunits 1 through 3. Black arrows: MT-ATP6 and MT-ATP8, subunits 6 and 8 of the mitochondrial ATPase, Red arrow: MT-CYB, cytochrome b. tRNAs are designated by green labels as per HGNC. Red broken line through MT-TL1, position of the bidirectional transcription terminator within MT-TL1. The putative D-Term transcription terminator is not shown as it has been described in murine mtDNA only.

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Figure 2. mtDNA organization around mitochondrial promoters in mouse and human cells. Nontemplate strand is shown. Transcription start sites are aligned and designated by a bent arrow at the top.5’ nucleotides of mitochondrial transcripts are green, bold and underlined (human and mouse HSP1 and LSP initiating nucleotides as per (96) and (63), respectively. hHSP2 as per (21)). Promoter sequences are enclosed into solid black boxes (hHSP1 and hLSP as per (96), mLSP and mHSP as per (25)). The sequence for the putative murine transcription termination site in the D-loop, D-TERM, is enclosed into a solid red box (46). Horizontal arrows, putative HMG binding sequences and their direction as per (59). Broken box, sequences that are important for preinitiation complex formation at mLSP as per (25). Red font, TFAM footprints as per (29). Broken lines underline TFAM footprints as per (58). Dotted line over the sequence, TFAM footprint as per (60). Broken arrow under the sequence, TFAM footprint as per (62).

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Figure 3. Amodel for mitochondrial transcription initiation. 1. TFAM binds to a high affinity binding site upstream of a mitochondrial promoter (designated by the bent arrow at the transcription start site) and induces a sharp bend in mtDNA; 2. POLRMT is recruited to the mtDNA/TFAM complex presumably through interaction with TFAM CTD; 3. Recruitment of the TFB2M to mtDNA/TFAM/POLRMT ternary complex facilitates promoter melting, recruitment of the initiating nucleotide, and initiates RNA synthesis (broken line).

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Figure 4. Structures of major proteins involved in the mitochondrial transcription. CTD, C-terminal domain; HhH, helix-hairpin-helix motif; HMG1 and2, high mobility group-like domain; MTS, matrix targeting sequence; NED, N-terminal extension domain; NTD, N-terminal domain; POLR, POLRMT binding domain of the TFB2M; PR, Promoter-interacting domain; PS, priming substrate-interacting domain; RNHF, RNaseH fold, RuvC type; SAM, S-adenosylmethionine-dependent methyltransferase-like domain; SL, specificity loop; TFB, TFB2M-binding domain.