Genotoxic stress increases cytoplasmic mitochondrial DNA editing by human APOBEC3 mutator enzymes at a single cell level

Scientific Reports
Bianka MussilJean-Pierre Vartanian

Abstract

Human cells are stressed by numerous mechanisms that can lead to leakage of mitochondrial DNA (mtDNA) to the cytoplasm and ultimately apoptosis. This agonist DNA constitutes a danger to the cell and is counteracted by cytoplasmic DNases and APOBEC3 cytidine deamination of DNA. To investigate APOBEC3 editing of leaked mtDNA to the cytoplasm, we performed a PCR analysis of APOBEC3 edited cytoplasmic mtDNA (cymtDNA) at the single cell level for primary CD4+ T cells and the established P2 EBV blast cell line. Up to 17% of primary CD4+ T cells showed signs of APOBEC3 edited cymtDNA with ~50% of all mtDNA sequences showing signs of APOBEC3 editing - between 1500-5000 molecules. Although the P2 cell line showed a much lower frequency of stressed cells, the number of edited mtDNA molecules in such cells was of the same order. Addition of the genotoxic molecules, etoposide or actinomycin D increased the number of cells showing APOBEC3 edited cymtDNA to around 40%. These findings reveal a very dynamic image of the mitochondrial network, which changes considerably under stress. APOBEC3 deaminases are involved in the catabolism of mitochondrial DNA to circumvent chronic immune stimulation triggered by released mitochondrial DNA from damage...Continue Reading

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Citations

Sep 24, 2020·International Journal of Molecular Sciences·Sergey BrezginVladimir Chulanov
Nov 16, 2019·BMC Genomics·Vincent CavalRodolphe Suspène
Aug 9, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Bartlomiej Swiatczak
Apr 14, 2021·Scientific Reports·Danielle Perez-BercoffSimon Wain-Hobson
Aug 7, 2021·Trends in Genetics : TIG·Karla Cervantes-GraciaRichard Chahwan
Aug 18, 2021·The Journal of Biological Chemistry·Vincent CavalSimon Wain-Hobson
Oct 31, 2019·Chemical Research in Toxicology·Li TaoYanqing Liu

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Methods Mentioned

BETA
deamination
PCR
FACS
transfection
flow cytometry

Clinical Trials Mentioned

NCT00698919

Software Mentioned

Diagmicoll
CellQuest Pro
FlowJo

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis