Structural Basis of Mitochondrial Transcription Initiation

Hillen, Hauke S.; Morozov, Yaroslav I.; Sarfallah, Azadeh; Temiakov, Dmitry; Cramer, Patrick

doi:10.1016/j.cell.2017.10.036

Cited by 150 publications

(211 citation statements)

References 52 publications

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“…Although electron density resulting from X-ray diffraction for the linker is weak, in the cryoEM map at 3.9Å resolution, the linker threads through the inside of the DNA bulge, between RAG1 and the 23RSS (Fig. S2B), which is reminiscent of the binding of TFAM (an HMGB homolog) to the promoter DNA in the mitochondrial transcription initiation complex (Hillen et al, 2017). …”

Section: Resultsmentioning

confidence: 99%

“…1). In contrast, structures of TFAM, which also contains two HMG boxes, have been determined in complex with a transcription initiation site, where the DNA is bent 90° by each of the two HMG boxes in phase, making a 180° U-turn (Hillen et al, 2017; Rubio-Cosials et al, 2011). We notice that wherever TFAM bends the DNA, there is a CA or TG dinucleotide.…”

Section: Discussionmentioning

confidence: 99%

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Cracking the DNA Code for V(D)J Recombination

Kim

Chuenchor²,

Chen³

et al. 2018

Molecular Cell

117

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Summary To initiate V(D)J recombination for generating the adaptive immune response of vertebrates, RAG1/2 recombinase cleaves DNA at a pair of recombination signal sequences, the 12- and 23-RSS. We have determined crystal and cryoEM structures of RAG1/2 with DNA in the pre-reaction and hairpin-forming complexes up to 2.75Å resolution. Both protein and DNA exhibit structural plasticity and undergo dramatic conformational changes. Coding-flank DNAs rotate, shift and deform extensively for nicking and hairpin formation. Two intertwined RAG1 subunits crisscross four times between the asymmetric pair of severely bent 12/23-RSS DNAs. Location-sensitive bending of 60° and 150° in 12- and 23-RSS spacers, respectively, must occur for RAG1/2 to capture the nonamers and pair the heptamers for symmetric double-strand breakage. DNA pairing is thus sequence-context dependent and structure specific, which partly explains the “beyond 12/23” restriction. Finally, catalysis in crystallo reveals the process of DNA hairpin formation and its stabilization by interleaved base stacking.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cracking the DNA Code for V(D)J Recombination

Kim

Chuenchor²,

Chen³

et al. 2018

Molecular Cell

117

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“…TFAM‐binding causes a distortion of the mtDNA and results in DNA bending . This distortion enables the specific binding of POLRMT (mitochondrial RNA polymerase) to the start site, where TFAM binds to the N terminus of POLRMT to recruit TFB2M (mitochondrial transcription factor 2) while maintaining an open DNA complex arrangement that enables productive transcription initiation .…”

Section: Tfam Regulation Of Mtdnamentioning

confidence: 99%

The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

2018

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The mitochondrial transcription factor A, or TFAM, is a mitochondrial DNA (mtDNA)‐binding protein essential for genome maintenance. TFAM functions in determining the abundance of the mitochondrial genome by regulating packaging, stability, and replication. More recently, TFAM has been shown to play a central role in the mtDNA stress‐mediated inflammatory response. Emerging evidence indicates that decreased mtDNA copy number is associated with several aging‐related pathologies; however, little is known about the association of TFAM abundance and disease. In this Review, we evaluate the potential associations of altered TFAM levels or mtDNA copy number with neurodegeneration. We also describe potential mechanisms by which mtDNA replication, transcription initiation, and TFAM‐mediated endogenous danger signals may impact mitochondrial homeostasis in Alzheimer, Huntington, Parkinson, and other neurodegenerative diseases.

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“…Human mitochondrial transcription factor A (TFAM), encoded by the nuclear gene TFAM , is required for mitochondrial DNA replication and transcription, which are essential for mitochondrial biogenesis . The results from ONCOMINE database of cancer microarray assays show that TFAM is up‐regulated in a variety of tumour cell lines .…”

Section: Introductionmentioning

confidence: 99%

Down‐regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway

Jiang

Wang

2019

J Cellular Molecular Medi

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Mitochondrial transcription factor A (TFAM) is a key regulator of mitochondria biogenesis. Previous studies confirmed that reduced TFAM expression sensitized tumours cells to chemical therapy reagents and ionizing irradiation (IR). However, the underlying mechanisms remain largely unknown. In this study, we identified that decreased expression of TFAM impaired the proliferation of tumour cells by inducing G1/S phase arrest and reducing the expression of E2F1, phospo‐Rb, PCNA and TK1. Furthermore, we proved that knockdown of TFAM enhanced the interaction between p53 and MDM2, resulting in decreased expression of p53 and the downstream target TIGAR, and thus leading to elevated level of mitochondrial superoxide and DNA double‐strand break (DSB) which were exacerbated when treated the cell with ionizing radiation. Those indicated that knockdown of TFAM could aggravate radiation induced DSB levels through affecting the production of mitochondria derived reactive oxygen species. Our current work proposed a new mechanism that TFAM through p53/TIGAR signalling to regulate the sensitivity of tumour cells to ionizing radiation. This indicated that TFAM might be a potential target for increasing the sensitization of cancer cells to radiotherapy.

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Structural Basis of Mitochondrial Transcription Initiation

Cited by 150 publications

References 52 publications

Cracking the DNA Code for V(D)J Recombination

Cracking the DNA Code for V(D)J Recombination

The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms

Down‐regulation of TFAM increases the sensitivity of tumour cells to radiation via p53/TIGAR signalling pathway

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