Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine

Banda, Douglas M.; Nuñez, Nicole N.; Burnside, Michael A.; Bradshaw, Katie M.; David, Sheila S.

doi:10.1016/j.freeradbiomed.2017.01.008

Cited by 81 publications

(99 citation statements)

References 189 publications

(278 reference statements)

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“…The importance of MutY’s activity is demonstrated by near-universal homologue conservation from prokaryotes to eukaryotes, and by its disease-relevance in humans as exemplified by an inherited colorectal cancer syndrome known as MUTYH-associated polyposis, or MAP. 2,5−7 …”

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confidence: 99%

“…Along with a growing number of glycosylases, MutY contains a [4Fe–4S] 2+ cofactor that is required for activity. 7−11 MutY enzymes are also distinct from other BER glycosylases in possessing a unique C-terminal domain (CTD) that is highly homologous to the NUDIX d(OG)TP hydrolase NUDT1; moreover, the CTD has been shown to be crucial for OG recognition and repair. 12,13 Structural insights into the lesion recognition process have been provided by several crystal structures using either a cleavage-resistant 2′-deoxy-2′-fluoroadenosine analog, an inactive enzyme, or a transition state mimic to capture a glimpse of MutY on the cusp of catalysis.…”

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Structure–Activity Relationships Reveal Key Features of 8-Oxoguanine: A Mismatch Detection by the MutY Glycosylase

et al. 2017

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Base excision repair glycosylases locate and remove damaged bases in DNA with remarkable specificity. The MutY glycosylases, unusual for their excision of undamaged adenines mispaired to the oxidized base 8-oxoguanine (OG), must recognize both bases of the mispair in order to prevent promutagenic activity. Moreover, MutY must effectively find OG:A mismatches within the context of highly abundant and structurally similar T:A base pairs. Very little is known about the factors that initiate MutY’s interaction with the substrate when it first encounters an intrahelical OG:A mispair, or about the order of recognition checkpoints. Here, we used structure–activity relationships (SAR) to investigate the features that influence the in vitro measured parameters of mismatch affinity and adenine base excision efficiency by E. coli MutY. We also evaluated the impacts of the same substrate alterations on MutY-mediated repair in a cellular context. Our results show that MutY relies strongly on the presence of the OG base and recognizes multiple structural features at different stages of recognition and catalysis to ensure that only inappropriately mispaired adenines are excised. Notably, some OG modifications resulted in more dramatic reductions in cellular repair than in the in vitro kinetic parameters, indicating their importance for initial recognition events needed to locate the mismatch within DNA. Indeed, the initial encounter of MutY with its target base pair may rely on specific interactions with the 2-amino group of OG in the major groove, a feature that distinguishes OG:A from T:A base pairs. These results furthermore suggest that inefficient substrate location in human MutY homologue variants may prove predictive for the early onset colorectal cancer phenotype known as MUTYH-Associated Polyposis, or MAP.

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Structure–Activity Relationships Reveal Key Features of 8-Oxoguanine: A Mismatch Detection by the MutY Glycosylase

et al. 2017

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“…The chemical element (mineral) composition of E. teff seeds determined by PIXE and/or FAAS showed the presence of K, S, P, Ca, Mg, Fe, Mn, Zn, and Cu as important constituents (Table 1) which are used as cofactors by many enzymes, including DNA repair proteins. 22,23 All essential amino acids for the human nutrition were found in appreciable amounts in seeds (Table 2 and Fig. 1B), excepting tryptophan which could not be accessed with certainty due to the degradation of the acid hydrolysis step.…”

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Nutritional composition of Eragrostis teff and its association with the observed antimutagenic effects

et al. 2019

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“…In a study of PBMCs from 105 AD patients and 130 controls, the polymorphisms of c.580C>T and c.1196A>G of XRCC1 and c.977C>G of OGG1 are significantly associated with AD risk ( Table 2) [216]; both XRCC1 and OGG1 function in BER (Figure 3). In comparison to 110 controls, significant increases in 8-oxoG DNA content with concomitant downregulations of 8-oxoG DNA glycosylase OGG1 and MUTYH [217], other DNA glycosylase NEIL1, APE1, and PARP1 were demonstrated in the PBMCs of AD patients (n = 100) ( Table 2) [218,219]. Elevations in serum 8-OHdG was reported in AD patients (n = 30) compared to age-matched controls (n = 30) [220].…”

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Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

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Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine

Cited by 81 publications

References 189 publications

Structure–Activity Relationships Reveal Key Features of 8-Oxoguanine: A Mismatch Detection by the MutY Glycosylase

Structure–Activity Relationships Reveal Key Features of 8-Oxoguanine: A Mismatch Detection by the MutY Glycosylase

Nutritional composition of Eragrostis teff and its association with the observed antimutagenic effects

Contributions of DNA Damage to Alzheimer’s Disease

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