Specific Inhibition of NEIL-initiated Repair of Oxidized Base Damage in Human Genome by Copper and Iron

Hegde, Muralidhar L.; Hegde, Pavana M.; Holthauzen, Luis Marcelo F.; Hazra, Tapas K.; Rao, K. S.; Mitra, Sankar

doi:10.1074/jbc.m110.126664

Cited by 66 publications

(55 citation statements)

References 79 publications

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“…1D). Hegde et al reported that NEIL1 initiates repair of oxidized base damage is specifically inhibited by copper and iron (Hegde, Hegde et al 2010). Based on this, we initially hypothesized that the AD brains might have elevated iron deposition that may inhibit NEIL1 activity without loss of protein quantity.…”

Section: Discussionmentioning

confidence: 99%

Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease

Canugovi

Shamanna

Croteau

et al. 2014

Neurobiology of Aging

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Alzheimer’s disease (AD) is a senile dementia with increased incidence in older subjects (age>65 years). One of the earliest markers of AD is oxidative DNA damage. Recently it has been reported that preclinical AD patient brains show elevated levels of oxidative damage in both nuclear and mitochondrial nucleic acids. Moreover, different oxidative lesions in mitochondrial DNA are between 5–10-fold higher than in nuclear DNA in both control and AD postmortem brains. We previously showed that there is a significant loss of base excision repair (BER) components in whole tissue extracts of AD and mild cognitive impairment subjects relative to matched control subjects. However, comprehensive analysis of specific steps in base excision repair levels in mitochondrial extracts of AD patient brains is not available. In this study we mainly investigated various components of BER in mitochondrial extracts of AD and matched control postmortem brain samples. We found that the 5-hydroxyuracil (5OHU) incision and ligase activities are significantly lower in AD brains whereas the uracil incision, abasic site cleavage and dNTP incorporation activities are normal in these samples.

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Section: Discussionmentioning

confidence: 99%

Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease

Canugovi

Shamanna

Croteau

et al. 2014

Neurobiology of Aging

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“…General reduction in DNA repair capacity during ageing and in sporadic NDDs could involve multiple mechanisms including, (i) altered transcriptional regulation causing reduced expression of a repair protein (e.g., reduced levels of MRN, DNA-PKcs [143, 163] in CS; reduced OGG1 (in mitochondria) [164] and Polβ in AD [165], reduced breast cancer associated gene 1 (BRCA1) in AD brain [166]); (ii) inhibition of catalytic activity of repair proteins, whose levels are otherwise comparable to healthy neurons in the CNS, primarily by NDD-linked etiological factors like exposure to excessive pro-oxidant metals and ROS (e.g., metal and ROS-mediated inhibition of NEIL1, NEIL2, LigIII, APE1 etc., in AD and PD [167, 168]; reduced catalytic activity of OGG1 in AD [136, 169] and reduced Polβ activity in AD [136, 165] and (iii) abnormal degradation and/or mis-localization of repair proteins (e.g., degradation of ATM and PARP1 by caspases/Matrix-Metallo-Proteinases (MMPs) [170], nuclear to cytoplasmic mis-localization of FUS in ALS [13]. Most of the NDDs have complex etiologies including oxidative stress, pro-oxidant metal and other toxic free radicals, and the misfolded/aggregating protein response, together with extensive accumulation of various types of DNA damages [18].…”

Section: Dna Repair Defects and Neuronal Phenotypesmentioning

confidence: 99%

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

Weng

Dharmalingam

Vasquez

et al. 2017

Mechanisms of Ageing and Development

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A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated ageing and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.

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“…Based on the relative success of synthetic lethality of PARP inhibitors with drug/radiation treatment of BRCA-negative breast cancer [174], BER/SSBR inhibitors could also provide effective alternative synthetic lethality strategy. In particular, DNA glycosylases, which we showed to regulate and control the complete repair sub-pathways [68,175,31] and/or DNA ligase III/DNA ligase I, the two key nick-sealing enzymes [176,177] have strong potential as synthetic lethality targets which is currently being explored by our and others’ laboratories.…”

Section: Ber/ssbr An Attractive Anti-cancer Target In Synthetic Lethmentioning

confidence: 99%

New paradigms in the repair of oxidative damage in human genome: mechanisms ensuring repair of mutagenic base lesions during replication and involvement of accessory proteins

Dutta

Yang

Sengupta

et al. 2015

Cell. Mol. Life Sci.

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Oxidized bases in the mammalian genome, which are invariably mutagenic due to their mis-pairing property, are continuously induced by endogenous reactive oxygen species (ROS) and more abundantly after oxidative stress. Unlike bulky base adducts induced by UV and other environmental mutagens in the genome that block replicative DNA polymerases, oxidatively damaged bases such as 5-hydoxyuracil (5-OHU), produced by oxidative deamination of cytosine in the template strand, do not block replicative polymerases and thus need to be repaired prior to replication in order to prevent mutation. Following up our earlier studies, which showed that the Nei endonuclease VIII like 1 (NEIL1) DNA glycosylase, one of five base excision repair (BER)-initiating enzymes in mammalian cells, has enhanced expression during the S-phase and higher affinity for replication fork-mimicking single-stranded (ss) DNA substrates, we recently provided direct experimental evidence for NEIL1’s role in replicating template-strand repair. The key requirement for this event, which we named as the ‘cow-catcher’ mechanism of pre-replicative BER, is NEIL1’s non-productive binding (substrate binding without product formation) to the lesion base in ss DNA template to stall DNA synthesis, causing fork regression. Repair of the lesion in re-annealed duplex is then carried out by NEIL1 in association with the DNA replication proteins. NEIL1 (and other BER-initiating enzymes) also interact with several accessory and non-canonical proteins including the heterogeneous nuclear ribonucleoprotein U (hnRNP-U) and Y-box-binding protein 1 (YB-1) as well as high mobility group box 1 protein (HMGB1), whose precise roles in BER are still obscure. In this review, we have discussed the recent advances in our understanding of oxidative genome damage repair pathways with particular focus on the pre-replicative template strand repair and the role of scaffold factors like X-ray repair cross-complementing protein 1 (XRCC1) and Poly [ADP-ribose] polymerase 1 (PARP1) and other accessory proteins guiding distinct BER sub-pathways.

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Specific Inhibition of NEIL-initiated Repair of Oxidized Base Damage in Human Genome by Copper and Iron

Cited by 66 publications

References 79 publications

Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease

Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

New paradigms in the repair of oxidative damage in human genome: mechanisms ensuring repair of mutagenic base lesions during replication and involvement of accessory proteins

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