8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair

Abstract

8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2′-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress.

Oxidative DNA damage in disease—Insights gained from base excision repair glycosylase‐deficient mouse models

“…MUTY, which catalyzes the removal of a misincorporated adenine opposite 8-oxoG, has been shown to increase the formation of single-strand breaks in both nuclear and mtDNA, thereby triggering cell death in cells accumulating high levels of 8-oxoG [Oka et al, 2008]. Interestingly, in this study, MutY 2/2 and Ogg1 2/2 ;MutY 2/2 double knockout mice were significantly protected from the neurodegenerative effects of 3-NP exposure, suggesting that while OGG1 and MTH1 are protective against oxidative stress, MUTY-mediated repair of mispaired adenines across from 8-oxoG residues may be directly implicated in the pathology of oxidative stress-induced neurodegeneration [Sheng et al, 2012]. It will be interesting to determine if this protective effect of MUTY is also important in models of neurodegeneration not induced by 3-NP exposure and therefore relevant to non-Huntington's related pathologies.…”

“…In this regard, both Mth1 2/2 mice, as well as Ogg1 2/2 ;Mth1 2/2 double knockout mice were shown to be prone to neurodegeneration under conditions of increased oxidative stress, induced by administration of 3-nitropropionic acid (3-NP), a mitochondrial toxin that has been used to model Huntington's disease. This worsening of striatal neurodegeneration was accompanied by increased 8-oxoG content in mtDNA but not in nuclear DNA of Ogg1 2/2 ;Mth1 2/2 double knockout mice exposed to oxidative stress [Sheng et al, 2012]. MUTY, which catalyzes the removal of a misincorporated adenine opposite 8-oxoG, has been shown to increase the formation of single-strand breaks in both nuclear and mtDNA, thereby triggering cell death in cells accumulating high levels of 8-oxoG [Oka et al, 2008].…”

MUTYH promotes oxidative microglial activation and inherited retinal degeneration

“…However, because various cell types could be affected by systemic Mutyh deficiency, we cannot exclude the possibility that MUTYH acts directly on photoreceptor cells and induces cell death in rd10 mice. MUTYH-mediated BER forms single-or double-stranded breaks of DNA and induces cell death under severe oxidative stress in diverse cell types, indicating these events as an important mechanism of cell death conserved from bacteria to mammals (21,23,40,41). Further studies using microglia-or photoreceptor-specific Mutyh KOs are needed to elucidate the precise mechanisms by which oxidative DNA damage promotes retinal inflammation and degeneration in rd10 mice.…”

“…formation of single-strand breaks (SSBs) of DNA during the BER process (21,22), and this causes neuronal cell death as well as microgliosis in toxin-induced neurodegeneration (23).…”

Oxidative stress and DNA damage induced by spinosad exposure in Spodoptera frugiperda Sf9 cells

“…Among the various types of oxidative lesions, 8-oxoguanine (8-oxoG) is one of the major oxidized base in both nucleotide pools and polymerized DNA, which is strongly mutagenic as it can mispair with adenine residues instead of the cysteine residues, leading to GC to AT transversion mutations (Leon et al, 2016). 8-oxoG-DNA glycosylase (OGG1) excises 8-oxoG paired with cytosine in DNA, and 8-oxoG nucleoside triphosphatase (MTH1) hydrolyzes 8-oxo-dGTP in nucleotide pools, avoid incorporation of 8-oxo-dGMP into DNA, thus preventing the accumulation of oxidative DNA damage (Sheng et al, 2012). DNA damage that is characterized by DNA strand breaks and chromosomal instability can lead to chromosome mis-segregation during mitosis and generate micronuclei (Bakhoum, Kabeche, Murnane, Zaki, & Compton, 2014).…”