The Fate of Oxidative Strand Breaks in Mitochondrial DNA

Mitochondrial DNA (mtDNA) is particularly vulnerable to somatic mutagenesis. Potential mechanisms include DNA polymerase γ (POLG) errors and the effects of mutagens, such as reactive oxygen species. Here, we studied the effects of transient hydrogen peroxide (H<sub<2</sub<O<sub<2&l...
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Autor*in:	Genevieve Trombly [verfasserIn] Afaf Milad Said [verfasserIn] Alexei P. Kudin [verfasserIn] Viktoriya Peeva [verfasserIn] Janine Altmüller [verfasserIn] Kerstin Becker [verfasserIn] Karl Köhrer [verfasserIn] Gábor Zsurka [verfasserIn] Wolfram S. Kunz [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	mitochondrial DNA oxidative damage mtDNA double-strand breaks mtDNA single-strand breaks mtDNA degradation

Übergeordnetes Werk:	In: Antioxidants - MDPI AG, 2013, 12(2023), 5, p 1087
Übergeordnetes Werk:	volume:12 ; year:2023 ; number:5, p 1087

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/antiox12051087

Katalog-ID:	DOAJ094427887

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callnumber-first	R - Medicine
author	Genevieve Trombly
spellingShingle	Genevieve Trombly misc RM1-950 misc mitochondrial DNA misc oxidative damage misc mtDNA double-strand breaks mtDNA single-strand breaks misc mtDNA degradation misc Therapeutics. Pharmacology The Fate of Oxidative Strand Breaks in Mitochondrial DNA
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topic_title	RM1-950 The Fate of Oxidative Strand Breaks in Mitochondrial DNA mitochondrial DNA oxidative damage mtDNA double-strand breaks mtDNA single-strand breaks mtDNA degradation
topic	misc RM1-950 misc mitochondrial DNA misc oxidative damage misc mtDNA double-strand breaks mtDNA single-strand breaks misc mtDNA degradation misc Therapeutics. Pharmacology
topic_unstemmed	misc RM1-950 misc mitochondrial DNA misc oxidative damage misc mtDNA double-strand breaks mtDNA single-strand breaks misc mtDNA degradation misc Therapeutics. Pharmacology
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title	The Fate of Oxidative Strand Breaks in Mitochondrial DNA
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title_full	The Fate of Oxidative Strand Breaks in Mitochondrial DNA
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title_sort	fate of oxidative strand breaks in mitochondrial dna
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title_auth	The Fate of Oxidative Strand Breaks in Mitochondrial DNA
abstract	Mitochondrial DNA (mtDNA) is particularly vulnerable to somatic mutagenesis. Potential mechanisms include DNA polymerase γ (POLG) errors and the effects of mutagens, such as reactive oxygen species. Here, we studied the effects of transient hydrogen peroxide (H<sub<2</sub<O<sub<2</sub< pulse) on mtDNA integrity in cultured HEK 293 cells, applying Southern blotting, ultra-deep short-read and long-read sequencing. In wild-type cells, 30 min after the H<sub<2</sub<O<sub<2</sub< pulse, linear mtDNA fragments appear, representing double-strand breaks (DSB) with ends characterized by short GC stretches. Intact supercoiled mtDNA species reappear within 2–6 h after treatment and are almost completely recovered after 24 h. BrdU incorporation is lower in H<sub<2</sub<O<sub<2</sub<-treated cells compared to non-treated cells, suggesting that fast recovery is not associated with mtDNA replication, but is driven by rapid repair of single-strand breaks (SSBs) and degradation of DSB-generated linear fragments. Genetic inactivation of mtDNA degradation in exonuclease deficient POLG p.D274A mutant cells results in the persistence of linear mtDNA fragments with no impact on the repair of SSBs. In conclusion, our data highlight the interplay between the rapid processes of SSB repair and DSB degradation and the much slower mtDNA re-synthesis after oxidative damage, which has important implications for mtDNA quality control and the potential generation of somatic mtDNA deletions.
abstractGer	Mitochondrial DNA (mtDNA) is particularly vulnerable to somatic mutagenesis. Potential mechanisms include DNA polymerase γ (POLG) errors and the effects of mutagens, such as reactive oxygen species. Here, we studied the effects of transient hydrogen peroxide (H<sub<2</sub<O<sub<2</sub< pulse) on mtDNA integrity in cultured HEK 293 cells, applying Southern blotting, ultra-deep short-read and long-read sequencing. In wild-type cells, 30 min after the H<sub<2</sub<O<sub<2</sub< pulse, linear mtDNA fragments appear, representing double-strand breaks (DSB) with ends characterized by short GC stretches. Intact supercoiled mtDNA species reappear within 2–6 h after treatment and are almost completely recovered after 24 h. BrdU incorporation is lower in H<sub<2</sub<O<sub<2</sub<-treated cells compared to non-treated cells, suggesting that fast recovery is not associated with mtDNA replication, but is driven by rapid repair of single-strand breaks (SSBs) and degradation of DSB-generated linear fragments. Genetic inactivation of mtDNA degradation in exonuclease deficient POLG p.D274A mutant cells results in the persistence of linear mtDNA fragments with no impact on the repair of SSBs. In conclusion, our data highlight the interplay between the rapid processes of SSB repair and DSB degradation and the much slower mtDNA re-synthesis after oxidative damage, which has important implications for mtDNA quality control and the potential generation of somatic mtDNA deletions.
abstract_unstemmed	Mitochondrial DNA (mtDNA) is particularly vulnerable to somatic mutagenesis. Potential mechanisms include DNA polymerase γ (POLG) errors and the effects of mutagens, such as reactive oxygen species. Here, we studied the effects of transient hydrogen peroxide (H<sub<2</sub<O<sub<2</sub< pulse) on mtDNA integrity in cultured HEK 293 cells, applying Southern blotting, ultra-deep short-read and long-read sequencing. In wild-type cells, 30 min after the H<sub<2</sub<O<sub<2</sub< pulse, linear mtDNA fragments appear, representing double-strand breaks (DSB) with ends characterized by short GC stretches. Intact supercoiled mtDNA species reappear within 2–6 h after treatment and are almost completely recovered after 24 h. BrdU incorporation is lower in H<sub<2</sub<O<sub<2</sub<-treated cells compared to non-treated cells, suggesting that fast recovery is not associated with mtDNA replication, but is driven by rapid repair of single-strand breaks (SSBs) and degradation of DSB-generated linear fragments. Genetic inactivation of mtDNA degradation in exonuclease deficient POLG p.D274A mutant cells results in the persistence of linear mtDNA fragments with no impact on the repair of SSBs. In conclusion, our data highlight the interplay between the rapid processes of SSB repair and DSB degradation and the much slower mtDNA re-synthesis after oxidative damage, which has important implications for mtDNA quality control and the potential generation of somatic mtDNA deletions.
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