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
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
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.
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U2 - 10.1074/jbc.M110.215715
DO - 10.1074/jbc.M110.215715
M3 - Article
C2 - 21768646
AN - SCOPUS:80052698492
SN - 0021-9258
VL - 286
SP - 31975
EP - 31983
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 37
ER -