Apoptosis induced by persistent single-strand breaks in mitochondrial genome: Critical role of EXOG (5′-exo/endonuclease) in their repair

Anne W. Tann, Istvan Boldogh, Gregor Meiss, Wei Qian, Bennett Van Houten, Sankar Mitra, Bartosz Szczesny

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

Reactive oxygen species (ROS), continuously generated as byproducts of respiration, inflict more damage on the mitochondrial (mt) than on the nuclear genome because of the nonchromatinized nature and proximity to the ROS source of the mitochondrial genome. Such damage, particularly single-strand breaks (SSBs) with 5′-blocking deoxyribose products generated directly or as repair intermediates for oxidized bases, is repaired via the base excision/SSB repair pathway in both nuclear and mt genomes. Here, we show that EXOG, a 5′-exo/endonuclease and unique to the mitochondria unlike FEN1 or DNA2, which, like EXOG, has been implicated in the removal of the 5′-blocking residue, is required for repairing endogenous SSBs in the mt genome. EXOG depletion induces persistent SSBs in the mtDNA, enhances ROS levels, and causes apoptosis in normal cells but not in mt genome-deficient rho0 cells. Thus, these data show for the first time that persistent SSBs in the mt genome alone could provide the initial trigger for apoptotic signaling in mammalian cells.

Original languageEnglish (US)
Pages (from-to)31975-31983
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number37
DOIs
StatePublished - Sep 16 2011

Fingerprint

Mitochondrial Genome
Endonucleases
Repair
Genes
Apoptosis
Reactive Oxygen Species
Deoxyribose
Mitochondria
Mitochondrial DNA
Respiration
Byproducts
Genome
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Apoptosis induced by persistent single-strand breaks in mitochondrial genome : Critical role of EXOG (5′-exo/endonuclease) in their repair. / Tann, Anne W.; Boldogh, Istvan; Meiss, Gregor; Qian, Wei; Van Houten, Bennett; Mitra, Sankar; Szczesny, Bartosz.

In: Journal of Biological Chemistry, Vol. 286, No. 37, 16.09.2011, p. 31975-31983.

Research output: Contribution to journalArticle

@article{83fc7cc2da6a4f6296075b3d03515380,
title = "Apoptosis induced by persistent single-strand breaks in mitochondrial genome: Critical role of EXOG (5′-exo/endonuclease) in their repair",
abstract = "Reactive oxygen species (ROS), continuously generated as byproducts of respiration, inflict more damage on the mitochondrial (mt) than on the nuclear genome because of the nonchromatinized nature and proximity to the ROS source of the mitochondrial genome. Such damage, particularly single-strand breaks (SSBs) with 5′-blocking deoxyribose products generated directly or as repair intermediates for oxidized bases, is repaired via the base excision/SSB repair pathway in both nuclear and mt genomes. Here, we show that EXOG, a 5′-exo/endonuclease and unique to the mitochondria unlike FEN1 or DNA2, which, like EXOG, has been implicated in the removal of the 5′-blocking residue, is required for repairing endogenous SSBs in the mt genome. EXOG depletion induces persistent SSBs in the mtDNA, enhances ROS levels, and causes apoptosis in normal cells but not in mt genome-deficient rho0 cells. Thus, these data show for the first time that persistent SSBs in the mt genome alone could provide the initial trigger for apoptotic signaling in mammalian cells.",
author = "Tann, {Anne W.} and Istvan Boldogh and Gregor Meiss and Wei Qian and {Van Houten}, Bennett and Sankar Mitra and Bartosz Szczesny",
year = "2011",
month = "9",
day = "16",
doi = "10.1074/jbc.M110.215715",
language = "English (US)",
volume = "286",
pages = "31975--31983",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "37",

}

TY - JOUR

T1 - Apoptosis induced by persistent single-strand breaks in mitochondrial genome

T2 - Critical role of EXOG (5′-exo/endonuclease) in their repair

AU - Tann, Anne W.

AU - Boldogh, Istvan

AU - Meiss, Gregor

AU - Qian, Wei

AU - Van Houten, Bennett

AU - Mitra, Sankar

AU - Szczesny, Bartosz

PY - 2011/9/16

Y1 - 2011/9/16

N2 - Reactive oxygen species (ROS), continuously generated as byproducts of respiration, inflict more damage on the mitochondrial (mt) than on the nuclear genome because of the nonchromatinized nature and proximity to the ROS source of the mitochondrial genome. Such damage, particularly single-strand breaks (SSBs) with 5′-blocking deoxyribose products generated directly or as repair intermediates for oxidized bases, is repaired via the base excision/SSB repair pathway in both nuclear and mt genomes. Here, we show that EXOG, a 5′-exo/endonuclease and unique to the mitochondria unlike FEN1 or DNA2, which, like EXOG, has been implicated in the removal of the 5′-blocking residue, is required for repairing endogenous SSBs in the mt genome. EXOG depletion induces persistent SSBs in the mtDNA, enhances ROS levels, and causes apoptosis in normal cells but not in mt genome-deficient rho0 cells. Thus, these data show for the first time that persistent SSBs in the mt genome alone could provide the initial trigger for apoptotic signaling in mammalian cells.

AB - Reactive oxygen species (ROS), continuously generated as byproducts of respiration, inflict more damage on the mitochondrial (mt) than on the nuclear genome because of the nonchromatinized nature and proximity to the ROS source of the mitochondrial genome. Such damage, particularly single-strand breaks (SSBs) with 5′-blocking deoxyribose products generated directly or as repair intermediates for oxidized bases, is repaired via the base excision/SSB repair pathway in both nuclear and mt genomes. Here, we show that EXOG, a 5′-exo/endonuclease and unique to the mitochondria unlike FEN1 or DNA2, which, like EXOG, has been implicated in the removal of the 5′-blocking residue, is required for repairing endogenous SSBs in the mt genome. EXOG depletion induces persistent SSBs in the mtDNA, enhances ROS levels, and causes apoptosis in normal cells but not in mt genome-deficient rho0 cells. Thus, these data show for the first time that persistent SSBs in the mt genome alone could provide the initial trigger for apoptotic signaling in mammalian cells.

UR - http://www.scopus.com/inward/record.url?scp=80052698492&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052698492&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.215715

DO - 10.1074/jbc.M110.215715

M3 - Article

C2 - 21768646

AN - SCOPUS:80052698492

VL - 286

SP - 31975

EP - 31983

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 37

ER -