WRN Exonuclease activity is blocked by specific oxidatively induced base lesions positioned in either DNA strand

Bukowy, Zuzanna; Harrigan, Jeanine A.; Ramsden, Dale A.; Tudek, Barbara; Bohr, Vilhelm A.; Stevnsner, Tinna

doi:10.1093/nar/gkn468

Cited by 27 publications

(26 citation statements)

References 67 publications

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“…Thus, the WS-associated genetic defect is related to impaired maintenance of DNA integrity, and has implications for the presence of oxidative stress in the WS phenotype (von Kobbe et al 2004). The roles of oxidative stress in WS have been investigated in studies of WRNp functions (von Kobbe et al 2004;Bukowy et al 2008;Harrigan et al 2007), consistent with in vitro (Davis and Kipling 2009) and animal studies (Deschênes et al 2005;Massip et al 2006;Moore et al 2008). Our previous reports provided evidence for excess oxidative stress in blood cells and body fluids from WS patients versus controls and versus patients with other genetic diseases (Pagano et al 2005b;Lloret et al 2008a).…”

Section: The Ws-mitochondria Puzzlementioning

confidence: 71%

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

et al. 2010

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Oxidative stress is a phenotypic hallmark in several genetic disorders characterized by cancer predisposition and/or propensity to premature ageing. Here we review the published evidence for the involvement of oxidative stress in the phenotypes of Ataxia-Telangiectasia (A-T), Down Syndrome (DS), Fanconi Anaemia (FA), and Werner Syndrome (WS), from the viewpoint of mitochondrial dysfunction. Mitochondria are recognized as both the cell compartment where energetic metabolism occurs and as the first and most susceptible target of reactive oxygen species (ROS) formation. Thus, a critical evaluation of the basic mechanisms leading to an in vivo pro-oxidant state relies on elucidating the features of mitochondrial impairment in each disorder. The evidence for different mitochondrial dysfunctions reported in A-T, DS, and FA is reviewed. In the case of WS, clear-cut evidence linking human WS phenotype to mitochondrial abnormalities is lacking so far in the literature. Nevertheless, evidence relating mitochondrial dysfunctions to normal ageing suggests that WS, as a progeroid syndrome, is likely to feature mitochondrial abnormalities. Hence, ad hoc research focused on elucidating the nature of mitochondrial dysfunction in WS pathogenesis is required. Based on the recognized, or reasonably suspected, role of mitochondrial abnormalities in the pathogenesis of these disorders, studies of chemoprevention with mitochondria-targeted supplements are warranted.

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Section: The Ws-mitochondria Puzzlementioning

confidence: 71%

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

et al. 2010

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“…35). Base adducts, such as 8-oxo-purines and Fapy lesions, associate stably with the WRN protein, and the subsequent complexes are believed to trigger/initiate base excision repair (24,35,39,67). In the absence (or reduction) of WRN, base lesions may accumulate, thereby increasing the mutation frequency.…”

Section: Discussionmentioning

confidence: 99%

Non-B DNA-forming Sequences and WRN Deficiency Independently Increase the Frequency of Base Substitution in Human Cells

Bacolla

Wang

Jain

et al. 2011

Journal of Biological Chemistry

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Although alternative DNA secondary structures (non-B DNA) can induce genomic rearrangements, their associated mutational spectra remain largely unknown. The helicase activity of WRN, which is absent in the human progeroid Werner syndrome, is thought to counteract this genomic instability. We determined non-B DNA-induced mutation frequencies and spectra in human U2OS osteosarcoma cells and assessed the role of WRN in isogenic knockdown (WRN-KD) cells using a supF gene mutation reporter system flanked by triplex-or Z-DNA-forming sequences. Although both non-B DNA and WRN-KD served to increase the mutation frequency, the increase afforded by WRN-KD was independent of DNA structure despite the fact that purified WRN helicase was found to resolve these structures in vitro. In U2OS cells, ϳ70% of mutations comprised single-base substitutions, mostly at G⅐C basepairs, with the remaining ϳ30% being microdeletions. The number of mutations at G⅐C base-pairs in the context of NGNN/ NNCN sequences correlated well with predicted free energies of base stacking and ionization potentials, suggesting a possible origin via oxidation reactions involving electron loss and subsequent electron transfer (hole migration) between neighboring bases. A set of ϳ40,000 somatic mutations at G⅐C base pairs identified in a lung cancer genome exhibited similar correlations, implying that hole migration may also be involved. We conclude that alternative DNA conformations, WRN deficiency and lung tumorigenesis may all serve to increase the mutation rate by promoting, through diverse pathways, oxidation reactions that perturb the electron orbitals of neighboring bases. It follows that such "hole migration" is likely to play a much more widespread role in mutagenesis than previously anticipated.The application of high resolution array comparative genomic hybridization techniques has revealed the frequent occurrence of DNA sequence motifs capable of forming alternative (non-B) DNA conformations (e.g. triplex, quadruplex, Z-DNA, cruciforms, slipped structures) at the breakpoint junctions of chromosomal alterations (gross deletions and duplications) associated with human genetic disease, including cystic fibrosis, mental retardation, and multiple congenital anomalies (1). These observations have served to extend the generality of previous work that aimed to elucidate the molecular mechanisms underlying recurrent translocations (2-6) and the genetic instability observed in many model systems (7-16), both of which were suggestive of a direct mutagenic role for non-B DNA. In the same vein, analyses of DNA sequence motifs flanking human gross deletion breakpoints (9), genomic inversions that distinguish the human from the chimpanzee genome (17), and DNA sequence tracts involved in pathological gene conversion events (18) have provided evidence for a wide ranging role for DNA secondary structure in promoting gross genomic rearrangements. Despite these recent advances, few studies (8, 11) have attempted to address systematically the extent of the influence ...

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“…Certain oxidative DNA lesions with OH groups at the C8 position in the major groove of DNA can block the exonuclease activity (Machwe et al, 2000). However, the presence of Ku70-80 can stimulate the WRN exonuclease to bypass these lesions (Bukowy et al, 2008). The interaction between Ku70-80 may therefore be important in the context of DSBs induced by both ionizing radiation and radiomimetic drugs, which are known to generate oxidatively induced base lesions in addition to DNA strand breaks.…”

Section: Recq Helicase Disordersmentioning

confidence: 99%

DNA repair deficiency in neurodegeneration

Jeppesen

Bohr

Stevnsner

2011

Progress in Neurobiology

302

268

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Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington’s disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.

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WRN Exonuclease activity is blocked by specific oxidatively induced base lesions positioned in either DNA strand

Cited by 27 publications

References 67 publications

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

Non-B DNA-forming Sequences and WRN Deficiency Independently Increase the Frequency of Base Substitution in Human Cells

DNA repair deficiency in neurodegeneration

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