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• W3164897961 endingPage "821" @default.
• W3164897961 startingPage "812" @default.
• W3164897961 abstract "Mitochondrial DNA (mtDNA) is present at high cellular copy number and more prone to damage than nuclear DNA (nDNA), characteristics consistent with a genotoxic stress sentinel function. mtDNA can be released from mitochondria into the cytoplasm and can therefore act as a second messenger signaling molecule. Cytoplasmic mtDNA engages innate immune nucleic acid sensors and upregulates interferon-stimulated (and other) genes that have roles in nuclear DNA repair. While clearly beneficial in terms of adaptive stress responses and genome stability, an mtDNA genotoxic stress sentinel function may contribute to cancer chemoresistance, chronic inflammation, and aging. High copy number, damage prone, and lean on repair mechanisms are unique features of mitochondrial DNA (mtDNA) that are hard to reconcile with its essentiality for oxidative phosphorylation, the primary function ascribed to this maternally inherited component of our genome. We propose that mtDNA is also a genotoxic stress sentinel, as well as a direct second messenger of this type of cellular stress. Here, we discuss existing evidence for this sentinel/effector role through the ability of mtDNA to escape the confines of the mitochondrial matrix and activate nuclear DNA damage/repair responses via interferon-stimulated gene products and other downstream effectors. However, this arrangement may come at a cost, leading to cancer chemoresistance and contributing to inflammation, disease pathology, and aging. High copy number, damage prone, and lean on repair mechanisms are unique features of mitochondrial DNA (mtDNA) that are hard to reconcile with its essentiality for oxidative phosphorylation, the primary function ascribed to this maternally inherited component of our genome. We propose that mtDNA is also a genotoxic stress sentinel, as well as a direct second messenger of this type of cellular stress. Here, we discuss existing evidence for this sentinel/effector role through the ability of mtDNA to escape the confines of the mitochondrial matrix and activate nuclear DNA damage/repair responses via interferon-stimulated gene products and other downstream effectors. However, this arrangement may come at a cost, leading to cancer chemoresistance and contributing to inflammation, disease pathology, and aging. a DNA repair mechanism involving the excision of oxidized bases (and other types of damaged bases) that do not distort the DNA helix to a large extent from DNA. (2′-3′-cyclic GMP-AMP) an unusual cyclic dinucleotide produced by cGAS that acts as a second messenger to activate innate immune signaling by binding to STING. (cyclic GMP-AMP synthase) an innate immune nucleic acid sensor that primarily binds DNA and produces the cyclic dinucleotide cGAMP. instability of DNA due to exposure to toxic endogenous or environmental agents. exchange between two similar or identical DNA strands, which is one mechanism to repair double-strand DNA breaks. cytoplasmic multiprotein complexes of the innate immune system that promote the production of mature interleukin (IL)-1β and IL-18. a DNA repair pathway for removal of bulky, helix-distorting lesions. the transmission of signals from mitochondria to the nucleus to modulate expression of nuclear genes required to maintain mitochondrial homeostasis or change mitochondrial biogenesis and/or function in response to physiological cues or stress conditions. (stimulator of interferon genes) an endoplasmic reticulum-associated protein of the innate immune system that binds to cyclic dinucleotides, such as cGAMP, to mediate the production of type I interferons and proinflammatory cytokines." @default.
• W3164897961 created "2021-06-07" @default.
• W3164897961 creator A5005672474 @default.
• W3164897961 creator A5079476247 @default.
• W3164897961 creator A5087435298 @default.
• W3164897961 date "2021-10-01" @default.
• W3164897961 modified "2023-10-18" @default.
• W3164897961 title "Mitochondrial DNA: cellular genotoxic stress sentinel" @default.
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