DNA-protein cross-links between abasic DNA damage and mitochondrial transcription factor A (TFAM).
Nucleic Acids Res
; 51(1): 41-53, 2023 01 11.
Article
em En
| MEDLINE
| ID: mdl-36583367
ABSTRACT
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,ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Mitocondriais
/
Reparo do DNA
Limite:
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos