Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical-induced DNA damage.

Science Advances
Shih-Chieh ChiangSherif El-Khamisy

Abstract

Breakage of one strand of DNA is the most common form of DNA damage. Most damaged DNA termini require end-processing in preparation for ligation. The importance of this step is highlighted by the association of defects in the 3'-end processing enzyme tyrosyl DNA phosphodiesterase 1 (TDP1) and neurodegeneration and by the cytotoxic induction of protein-linked DNA breaks (PDBs) and oxidized nucleic acid intermediates during chemotherapy and radiotherapy. Although much is known about the repair of PDBs in the nucleus, little is known about this process in the mitochondria. We reveal that TDP1 resolves mitochondrial PDBs (mtPDBs), thereby promoting mitochondrial gene transcription. Overexpression of a toxic form of mitochondrial topoisomerase I (TOP1mt*), which generates excessive mtPDBs, results in a TDP1-dependent compensatory up-regulation of mitochondrial gene transcription. In the absence of TDP1, the imbalance in transcription of mitochondrial- and nuclear-encoded electron transport chain (ETC) subunits results in misassembly of ETC complex III. Bioenergetics profiling further reveals that TDP1 promotes oxidative phosphorylation under both basal and high energy demands. It is known that mitochondrial dysfunction results in fr...Continue Reading

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Citations

Jan 19, 2018·International Journal of Environmental Research and Public Health·Xin LiChunyan Zhao
Apr 28, 2019·International Journal of Molecular Sciences·Steffi GoffartJaakko L O Pohjoismäki
Jun 23, 2019·International Journal of Molecular Sciences·Shar-Yin Naomi Huang, Yves Pommier
Jul 18, 2017·Nature Neuroscience·Callum WalkerSherif F El-Khamisy
Dec 8, 2017·Nucleic Acids Research·Ajinkya S Kawale, Lawrence F Povirk
May 22, 2019·Translational Neurodegeneration·Luis Bermúdez-Guzmán, Alejandro Leal
Mar 28, 2018·Brain : a Journal of Neurology·Callum Walker, Sherif F El-Khamisy
Feb 19, 2021·Matrix Biology : Journal of the International Society for Matrix Biology·Thomas Juretschke, Petra Beli
Nov 22, 2017·Current Opinion in Toxicology·Bennett Van HoutenMauricio Camargo
May 22, 2021·Antioxidants & Redox Signaling·Gustavo CarvalhoPaulina H Wanrooij

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Methods Mentioned

BETA
reverse transcription PCR
electron spin resonance
ESR
Assay
PCR
electrophoresis
ChIP
Fluorescence

Software Mentioned

LI
ImageJ
Comet Assay IV
GraphPad
COR Image Studio Lite
GraphPad Prism
PHERAstar
IN Cell Developer

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