Associations between DNA Damage, DNA Base Excision Repair Gene Variability and Alzheimer's Disease Risk

2016 ◽  
Vol 41 (3-4) ◽  
pp. 152-171 ◽  
Author(s):  
Dominik Kwiatkowski ◽  
Piotr Czarny ◽  
Monika Toma ◽  
Natalia Jurkowska ◽  
Agnieszka Sliwinska ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Lesions ◽  
Polymorphic Variants ◽  
Base Excision

Background: Increased oxidative damage to DNA is one of the pathways involved in Alzheimer's disease (AD). Insufficient base excision repair (BER) is in part responsible for increased oxidative DNA damage. The aim of the present study was to assess the effect of polymorphic variants of BER-involved genes and the peripheral markers of DNA damage and repair in patients with AD. Material and Methods: Comet assays and TaqMan probes were used to assess DNA damage, BER efficiency and polymorphic variants of 12 BER genes in blood samples from 105 AD patients and 130 controls. The DNA repair efficacy (DRE) was calculated according to a specific equation. Results: The levels of endogenous and oxidative DNA damages were higher in AD patients than controls. The polymorphic variants of XRCC1 c.580C>T XRCC1 c.1196A>G and OGG1 c.977C>G are associated with increased DNA damage in AD. Conclusion: Our results show that oxidative stress and disturbances in DRE are particularly responsible for the elevated DNA lesions in AD. The results suggest that oxidative stress and disruption in DNA repair may contribute to increased DNA damage in AD patients and risk of this disease. In addition, disturbances in DRE may be associated with polymorphisms of OGG1 and XRCC1.

scholarly journals Dynamic Compartmentalization of Base Excision Repair Proteins in Response to Nuclear and Mitochondrial Oxidative Stress

2008 ◽  
Vol 29 (3) ◽  
pp. 794-807 ◽  
Author(s):  
Lyra M. Griffiths ◽  
Dan Swartzlander ◽  
Kellen L. Meadows ◽  
Keith D. Wilkinson ◽  
Anita H. Corbett ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Intracellular Localization ◽  
Genotoxic Stress ◽  
Mitochondrial Oxidative Stress ◽  
Base Excision

ABSTRACT DNAs harbored in both nuclei and mitochondria of eukaryotic cells are subject to continuous oxidative damage resulting from normal metabolic activities or environmental insults. Oxidative DNA damage is primarily reversed by the base excision repair (BER) pathway, initiated by N-glycosylase apurinic/apyrimidinic (AP) lyase proteins. To execute an appropriate repair response, BER components must be distributed to accommodate levels of genotoxic stress that may vary considerably between nuclei and mitochondria, depending on the growth state and stress environment of the cell. Numerous examples exist where cells respond to signals, resulting in relocalization of proteins involved in key biological transactions. To address whether such dynamic localization contributes to efficient organelle-specific DNA repair, we determined the intracellular localization of the Saccharomyces cerevisiae N-glycosylase/AP lyases, Ntg1 and Ntg2, in response to nuclear and mitochondrial oxidative stress. Fluorescence microscopy revealed that Ntg1 is differentially localized to nuclei and mitochondria, likely in response to the oxidative DNA damage status of the organelle. Sumoylation is associated with targeting of Ntg1 to nuclei containing oxidative DNA damage. These studies demonstrate that trafficking of DNA repair proteins to organelles containing high levels of oxidative DNA damage may be a central point for regulating BER in response to oxidative stress.

scholarly journals The senescence-accelerated mouse prone 8 as a model for oxidative stress and impaired DNA repair in the male germ line

Reproduction ◽  
2013 ◽  
Vol 146 (3) ◽  
pp. 253-262 ◽  
Author(s):  
T B Smith ◽  
G N De Iuliis ◽  
T Lord ◽  
R J Aitken
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Reactive Oxygen Species Generation ◽  
Control Strain ◽  
Base Excision ◽  
High Level ◽  
Senescence Accelerated Mouse

The discovery of a truncated base excision repair pathway in human spermatozoa mediated by OGG1 has raised questions regarding the effect of mutations in critical DNA repair genes on the integrity of the paternal genome. The senescence-accelerated mouse prone 8 (SAMP8) is a mouse model containing a suite of naturally occurring mutations resulting in an accelerated senescence phenotype largely mediated by oxidative stress, which is further enhanced by a mutation in theOgg1gene, greatly reducing the ability of the enzyme to excise 8-hydroxy,2′-deoxyguanosine (8OHdG) adducts. An analysis of the reproductive phenotype of the SAMP8 males revealed a high level of DNA damage in caudal epididymal spermatozoa as measured by the alkaline Comet assay. Furthermore, these lesions were confirmed to be oxidative in nature, as demonstrated by significant increases in 8OHdG adduct formation in the SAMP8 testicular tissue (P<0.05) as well as in mature spermatozoa (P<0.001) relative to a control strain (SAMR1). Despite this high level of oxidative DNA damage in spermatozoa, reactive oxygen species generation was not elevated and motility of spermatozoa was found to be similar to that for the control strain with the exception of progressive motility, which exhibited a slight but significant decline with advancing age (P<0.05). When challenged with Fenton reagents (H2O2and Fe2+), the SAMP8 spermatozoa demonstrated a highly increased susceptibility to formation of 8OHdG adducts compared with the controls (P<0.001). These data highlight the role of oxidative stress and OGG1-dependent base excision repair mechanisms in defining the genetic integrity of mammalian spermatozoa.

scholarly journals Databases and Bioinformatics Tools for the Study of DNA Repair

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Kaja Milanowska ◽  
Kristian Rother ◽  
Janusz M. Bujnicki
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Uv Light ◽  
Dna Lesions ◽  
Environmental Chemicals ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Repair Mechanisms ◽  
Base Excision

DNA is continuously exposed to many different damaging agents such as environmental chemicals, UV light, ionizing radiation, and reactive cellular metabolites. DNA lesions can result in different phenotypical consequences ranging from a number of diseases, including cancer, to cellular malfunction, cell death, or aging. To counteract the deleterious effects of DNA damage, cells have developed various repair systems, including biochemical pathways responsible for the removal of single-strand lesions such as base excision repair (BER) and nucleotide excision repair (NER) or specialized polymerases temporarily taking over lesion-arrested DNA polymerases during the S phase in translesion synthesis (TLS). There are also other mechanisms of DNA repair such as homologous recombination repair (HRR), nonhomologous end-joining repair (NHEJ), or DNA damage response system (DDR). This paper reviews bioinformatics resources specialized in disseminating information about DNA repair pathways, proteins involved in repair mechanisms, damaging agents, and DNA lesions.

scholarly journals Role of Base Excision Repair Pathway in the Processing of Complex DNA Damage Generated by Oxidative Stress and Anticancer Drugs

2021 ◽  
Vol 8 ◽  
Author(s):  
Yeldar Baiken ◽  
Damira Kanayeva ◽  
Sabira Taipakova ◽  
Regina Groisman ◽  
Alexander A. Ishchenko ◽  
...  
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Genome Instability ◽  
Excision Repair ◽  
Chromosomal Rearrangements ◽  
Strand Break ◽  
Dna Lesions ◽  
Complex Nature ◽  
Base Excision

Chemical alterations in DNA induced by genotoxic factors can have a complex nature such as bulky DNA adducts, interstrand DNA cross-links (ICLs), and clustered DNA lesions (including double-strand breaks, DSB). Complex DNA damage (CDD) has a complex character/structure as compared to singular lesions like randomly distributed abasic sites, deaminated, alkylated, and oxidized DNA bases. CDD is thought to be critical since they are more challenging to repair than singular lesions. Although CDD naturally constitutes a relatively minor fraction of the overall DNA damage induced by free radicals, DNA cross-linking agents, and ionizing radiation, if left unrepaired, these lesions cause a number of serious consequences, such as gross chromosomal rearrangements and genome instability. If not tightly controlled, the repair of ICLs and clustered bi-stranded oxidized bases via DNA excision repair will either inhibit initial steps of repair or produce persistent chromosomal breaks and consequently be lethal for the cells. Biochemical and genetic evidences indicate that the removal of CDD requires concurrent involvement of a number of distinct DNA repair pathways including poly(ADP-ribose) polymerase (PARP)-mediated DNA strand break repair, base excision repair (BER), nucleotide incision repair (NIR), global genome and transcription coupled nucleotide excision repair (GG-NER and TC-NER, respectively), mismatch repair (MMR), homologous recombination (HR), non-homologous end joining (NHEJ), and translesion DNA synthesis (TLS) pathways. In this review, we describe the role of DNA glycosylase-mediated BER pathway in the removal of complex DNA lesions.

scholarly journals The Influence of (5′R)- and (5′S)-5′,8-Cyclo-2′-Deoxyadenosine on UDG and hAPE1 Activity. Tandem Lesions are the Base Excision Repair System’s Nightmare

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1303 ◽  
Author(s):  
Karwowski
Keyword(s):  
Dna Damage ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Repair Process ◽  
Dna Lesions ◽  
Repair System ◽  
Base Excision ◽  
Base Excision Repair System ◽  
Tandem Lesions ◽  
Ap Site

DNA lesions are formed continuously in each living cell as a result of environmental factors, ionisation radiation, metabolic processes, etc. Most lesions are removed from the genome by the base excision repair system (BER). The activation of the BER protein cascade starts with DNA damage recognition by glycosylases. Uracil-DNA glycosylase (UDG) is one of the most evolutionary preserved glycosylases which remove the frequently occurring 2′-deoxyuridine from single (ss) and double-stranded (ds) oligonucleotides. Conversely, the unique tandem lesions (5′R)- and (5′S)-5′,8-cyclo-2′-deoxyadenosine (cdA) are not suitable substrates for BER machinery and are released from the genome by the nucleotide excision repair (NER) system. However, the cyclopurines appearing in a clustered DNA damage structure can influence the BER process of other lesions like dU. In this article, UDG inhibition by 5′S- and 5′R-cdA is shown and discussed in an experimental and theoretical manner. This phenomenon was observed when a tandem lesion appears in single or double-stranded oligonucleotides next to dU, on its 3′-end side. The cdA shift to the 5′-end side of dU in ss-DNA stops this effect in both cdA diastereomers. Surprisingly, in the case of ds-DNA, 5′S-cdA completely blocks uracil excision by UDG. Conversely, 5′R-cdA allows glycosylase for uracil removal, but the subsequently formed apurinic/apyrimidinic (AP) site is not suitable for human AP-site endonuclease 1 (hAPE1) activity. In conclusion, the appearance of the discussed tandem lesion in the structure of single or double-stranded DNA can stop the entire base repair process at its beginning, which due to UDG and hAPE1 inhibition can lead to mutagenesis. On the other hand, the presented results can cast some light on the UDG or hAPE1 inhibitors being used as a potential treatment.

scholarly journals New perspectives in cancer biology from a study of canonical and non-canonical functions of base excision repair proteins with a focus on early steps

Mutagenesis ◽  
2019 ◽  
Vol 35 (1) ◽  
pp. 129-149 ◽  
Author(s):  
Matilde Clarissa Malfatti ◽  
Giulia Antoniali ◽  
Marta Codrich ◽  
Silvia Burra ◽  
Giovanna Mangiapane ◽  
...  
Keyword(s):  
Dna Repair ◽  
Base Excision Repair ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Dna Lesions ◽  
Cancer Development ◽  
Dna Repair Enzymes ◽  
Repair Enzymes ◽  
Base Excision

Abstract Alterations of DNA repair enzymes and consequential triggering of aberrant DNA damage response (DDR) pathways are thought to play a pivotal role in genomic instabilities associated with cancer development, and are further thought to be important predictive biomarkers for therapy using the synthetic lethality paradigm. However, novel unpredicted perspectives are emerging from the identification of several non-canonical roles of DNA repair enzymes, particularly in gene expression regulation, by different molecular mechanisms, such as (i) non-coding RNA regulation of tumour suppressors, (ii) epigenetic and transcriptional regulation of genes involved in genotoxic responses and (iii) paracrine effects of secreted DNA repair enzymes triggering the cell senescence phenotype. The base excision repair (BER) pathway, canonically involved in the repair of non-distorting DNA lesions generated by oxidative stress, ionising radiation, alkylation damage and spontaneous or enzymatic deamination of nucleotide bases, represents a paradigm for the multifaceted roles of complex DDR in human cells. This review will focus on what is known about the canonical and non-canonical functions of BER enzymes related to cancer development, highlighting novel opportunities to understand the biology of cancer and representing future perspectives for designing new anticancer strategies. We will specifically focus on APE1 as an example of a pleiotropic and multifunctional BER protein.

Potentiation of Melphalan-Induced Cytotoxicity through Targeting of the Base Excision Repair Pathway in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4799-4799
Author(s):  
April M. Reed ◽  
Melissa L. Fishel ◽  
Mark R. Kelley ◽  
Rafat Abonour
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Side Effects ◽  
Small Molecule ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Chemotherapeutic Agents ◽  
Repair Pathways ◽  
Base Excision

Abstract Melphalan (M) is an active agent against multiple myeloma (MM). One of the obstacles with M treatment is the patient’s ability to tolerate side effects such as mucositis and pancytopenia. This is especially true for those patients >70 years of age. We hypothesize that potentiation of M-induced cytotoxicity is possible in MM with agents that target, and therefore further imbalance, multiple DNA repair pathways. A key protein in the Base Excision Repair (BER) pathway, Apurinic/apyrimidinic endonuclease/ redox factor (APE1/Ref-1 or APE1) plays a major role in the repair of damage caused by chemotherapeutic agents including M and Temozolomide (TMZ), interacts with a number of transcription factors (HIF1-a, p53, AP1, NFkB, etc) to regulate their function through oxidation/reduction (redox) signaling, and is overexpressed in refractory/relapsed MM cells. Furthermore, a reduction in APE1 protein sensitizes MM cells to melphalan indicating that inhibition of this protein may have therapeutic potential in MM. In order to decipher the importance of APE1’s redox and repair functions in MM cells’ response to DNA damage via melphalan and TMZ, we have available to us small molecule APE1 inhibitors that affect only the repair activity or only the redox activity of APE1. The mechanism of action of MLP is primarily via monoadduct leading to DNA interstrand cross-link (ICL) formation which is processed by the Nucleotide Excision Repair (NER) pathway. MLP also causes N7methyl-G and N3methyl-A adduct formation which are repaired by the BER pathway. For these studies, we treated RPMI 8226 cells with several chemotherapeutic agents: M; TMZ, which creates primarily N7methyl-G and N3methyl-A adducts; Methoxyamine (MX), which has been shown to inhibit further processing by the BER pathway; and a small molecule which blocks the redox function of APE1. Our purpose was to overwhelm the DNA repair pathways by causing the accumulation of DNA repair intermediates and inducing apoptosis. M-induced cytotoxicity is enhanced by TMZ (CI=0.08), MX (CI=0.89), and E3330 (CI=0.06), and this effect was synergistic as determined by CalcuSyn software which generates median effect and combinational index (CI) values, with CI<1 indicative of synergy. Using MX to inhibit APE1 in combination with TMZ results in an increase in DNA damage and an increase in apoptosis in 8226 cells. Furthermore, the combination of the redox inhibitor + MX which blocks both functions of APE1 also results in an increase in apoptosis in the MM cells. Further studies include the addition of M to these combinations that are demonstrating an increase in efficacy in MM cells. These results indicate that using these DNA repair-targeted agents in addition to MLP may be a feasible way to increase the effect of the M on MM cells. The potential advantages to patients would be that they would be able to tolerate more treatments and that the combination treatments would be more effective than treatment with M alone. We anticipate that effective modulation of M and/or TMZ will overcome resistance without compromising efficacy and help to alleviate some of the side effects patients have to endure with melphalan treatment. This may be particularly advantageous to the more elderly patients.

scholarly journals Modulation of the Apurinic/Apyrimidinic Endonuclease Activity of Human APE1 and of Its Natural Polymorphic Variants by Base Excision Repair Proteins

2020 ◽  
Vol 21 (19) ◽  
pp. 7147
Author(s):  
Olga A. Kladova ◽  
Irina V. Alekseeva ◽  
Murat Saparbaev ◽  
Olga S. Fedorova ◽  
Nikita A. Kuznetsov
Keyword(s):  
Dna Repair ◽  
Binding Site ◽  
Base Excision Repair ◽  
Protein Interactions ◽  
Excision Repair ◽  
Dna Glycosylases ◽  
Protein Protein Interactions ◽  
Dna Binding Site ◽  
Polymorphic Variants ◽  
Base Excision

Human apurinic/apyrimidinic endonuclease 1 (APE1) is known to be a critical player of the base excision repair (BER) pathway. In general, BER involves consecutive actions of DNA glycosylases, AP endonucleases, DNA polymerases, and DNA ligases. It is known that these proteins interact with APE1 either at upstream or downstream steps of BER. Therefore, we may propose that even a minor disturbance of protein–protein interactions on the DNA template reduces coordination and repair efficiency. Here, the ability of various human DNA repair enzymes (such as DNA glycosylases OGG1, UNG2, and AAG; DNA polymerase Polβ; or accessory proteins XRCC1 and PCNA) to influence the activity of wild-type (WT) APE1 and its seven natural polymorphic variants (R221C, N222H, R237A, G241R, M270T, R274Q, and P311S) was tested. Förster resonance energy transfer–based kinetic analysis of abasic site cleavage in a model DNA substrate was conducted to detect the effects of interacting proteins on the activity of WT APE1 and its single-nucleotide polymorphism (SNP) variants. The results revealed that WT APE1 activity was stimulated by almost all tested DNA repair proteins. For the SNP variants, the matters were more complicated. Analysis of two SNP variants, R237A and G241R, suggested that a positive charge in this area of the APE1 surface impairs the protein–protein interactions. In contrast, variant R221C (where the affected residue is located near the DNA-binding site) showed permanently lower activation relative to WT APE1, whereas neighboring SNP N222H did not cause a noticeable difference as compared to WT APE1. Buried substitution P311S had an inconsistent effect, whereas each substitution at the DNA-binding site, M270T and R274Q, resulted in the lowest stimulation by BER proteins. Protein–protein molecular docking was performed between repair proteins to identify amino acid residues involved in their interactions. The data uncovered differences in the effects of BER proteins on APE1, indicating an important role of protein–protein interactions in the coordination of the repair pathway.

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