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DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM)
In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental fact...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9841407/ https://www.ncbi.nlm.nih.gov/pubmed/36583367 http://dx.doi.org/10.1093/nar/gkac1214 |
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author | Xu, Wenyan Tang, Jin Zhao, Linlin |
author_facet | Xu, Wenyan Tang, Jin Zhao, Linlin |
author_sort | Xu, Wenyan |
collection | PubMed |
description | In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA–protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3′-phospho-α,β-unsaturated aldehyde (3′pUA) residue on SSB. The 3′pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3′pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA. |
format | Online Article Text |
id | pubmed-9841407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-98414072023-01-18 DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM) Xu, Wenyan Tang, Jin Zhao, Linlin Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry In higher eukaryotic cells, mitochondria are essential organelles for energy production, metabolism, and signaling. Mitochondrial DNA (mtDNA) encodes 13 protein subunits for oxidative phosphorylation and a set of tRNAs and rRNAs. mtDNA damage, sourced from endogenous chemicals and environmental factors, contributes to mitochondrial genomic instability, which has been associated with various mitochondrial diseases. DNA–protein cross-links (DPCs) are deleterious DNA lesions that threaten genomic integrity. Although much has been learned about the formation and repair of DPCs in the nucleus, little is known about DPCs in mitochondria. Here, we present in vitro and in cellulo data to demonstrate the formation of DPCs between a prevalent abasic (AP) DNA lesion and a DNA-packaging protein, mitochondrial transcription factor A (TFAM). TFAM cleaves AP-DNA and forms DPCs and single-strand breaks (SSB). Lys residues of TFAM are critical for the formation of TFAM-DPC and a reactive 3′-phospho-α,β-unsaturated aldehyde (3′pUA) residue on SSB. The 3′pUA residue reacts with two Cys of TFAM and contributes to the stable TFAM-DPC formation. Glutathione reacts with 3′pUA and competes with TFAM-DPC formation, corroborating our cellular experiments showing the accumulation of TFAM-DPCs under limiting glutathione. Our data point to the involvement of TFAM in AP-DNA turnover and fill a knowledge gap regarding the protein factors in processing damaged mtDNA. Oxford University Press 2022-12-30 /pmc/articles/PMC9841407/ /pubmed/36583367 http://dx.doi.org/10.1093/nar/gkac1214 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Chemical Biology and Nucleic Acid Chemistry Xu, Wenyan Tang, Jin Zhao, Linlin DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM) |
title | DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM) |
title_full | DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM) |
title_fullStr | DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM) |
title_full_unstemmed | DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM) |
title_short | DNA–protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM) |
title_sort | dna–protein cross-links between abasic dna damage and mitochondrial transcription factor a (tfam) |
topic | Chemical Biology and Nucleic Acid Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9841407/ https://www.ncbi.nlm.nih.gov/pubmed/36583367 http://dx.doi.org/10.1093/nar/gkac1214 |
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