• 8‐oxoguanine DNA glycosylase 1
• age‐related disorders
• inflammation
• oxidative DNA damage‐related diseases
• tumors

• DNA Glycosylases/metabolism
• DNA Glycosylases/antagonists & inhibitors
• Humans
• DNA Damage
• Oxidative Stress/drug effects
• Animals
• Neoplasms/drug therapy
• Inflammation/drug therapy
• Aging/metabolism
• Molecular Targeted Therapy

• Research Services and Knowledge Transfer Office, University of Macau
• 2024A1515012659 Natural Science Foundation of Guangdong Province
• 2024B03J1243 Guangzhou Municipal Science and Technology Bureau
• Science and Technology Major Project of Guangxi
• 82304698 National Natural Science Foundation of China
• 32300317 National Natural Science Foundation of China
• Fundo para o Desenvolvimento das Ciências e da Tecnologia
• 2021A1515110338 Basic and Applied Basic Research Foundation of Guangdong Province

• chromatin structure
• folate sensitivity
• mechanisms of fragility
• rare fragile sites
• repeat expansions

• DNA triplex
• Friedreich’s ataxia
• GAA repeat instability
• H-DNA
• Replication fork stalling
• Trinucleotide repeats

• DNA Replication
• Friedreich Ataxia/genetics
• Genome-Wide Association Study
• Humans
• Iron-Binding Proteins/genetics
• Trinucleotide Repeat Expansion

• R35 GM130322 NIGMS NIH HHS

Bromophenolic flame retardants (BFRs) are a large group of synthetic substances used in the industry in order to reduce the flammability of synthetic materials used in electrical and electronic devices, textiles, furniture and other everyday products. The presence of BFRs has been documented in the environment, food, drinking water, inhaled dust and the human body. Due to the widespread exposure of the general population to BFRs and insufficient knowledge on their toxic action, including genotoxic potential, we have compared the effect of tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), 2,4,6,-tribromophenol (2,4,6-TBP) and pentabromophenol (PBP) on DNA damage in human peripheral blood mononuclear cells (PBMCs) (playing a crucial role in the immune system) as well as examined underlying mechanism of action of these substances. The cells were incubated for 24 h with studied compounds in the concentrations ranging from 0.01 to 10 µg/mL. The study has shown that examined BFRs induced single and, to a lesser extent, double strand-breaks formation and caused oxidative damage to pyrimidines, and particularly to purines in the incubated cells. PBMCs efficiently repaired the DNA strand-breaks induced by BFRs, but they were unable to remove completely damaged DNA (except cells treated with TBBPS). The greatest changes in the above-mentioned parameters were observed in cells incubated with TBBPA, while the smallest in PBMCs treated with TBBPS. The results have also revealed that tested compounds do not form adducts with DNA in PBMCs, while the observed changes were the most probably induced by indirect DNA-damaging agents, such as ROS and other reactive species.

• DNA adducts
• DNA base oxidation
• DNA strand-breaks
• Tribromophenol
• pentabromophenol
• peripheral blood mononuclear cells
• tetrabromobisphenol A
• tetrabromobisphenol S

Telomeres are protective nucleoprotein structures that cap linear chromosome ends and safeguard genome stability. Progressive telomere shortening at each somatic cell division eventually leads to critically short and dysfunctional telomeres, which can contribute to either cellular senescence and aging, or tumorigenesis. Human reproductive cells, some stem cells, and most cancer cells, express the enzyme telomerase to restore telomeric DNA. Numerous studies have shown that oxidative stress caused by excess reactive oxygen species is associated with accelerated telomere shortening and dysfunction. Telomeric repeat sequences are remarkably susceptible to oxidative damage and are preferred sites for the production of the mutagenic base lesion 8-oxoguanine, which can alter telomere length homeostasis and integrity. Therefore, knowledge of the repair pathways involved in the processing of 8-oxoguanine at telomeres is important for advancing understanding of the pathogenesis of degenerative diseases and cancer associated with telomere instability. The highly conserved guanine oxidation (GO) system involves three specialized enzymes that initiate distinct pathways to specifically mitigate the adverse effects of 8-oxoguanine. Here we introduce the GO system and review the studies focused on investigating how telomeric 8-oxoguanine processing affects telomere integrity and overall genome stability. We also discuss newly developed technologies that target oxidative damage selectively to telomeres to investigate roles for the GO system in telomere stability.

• 8-oxoguanine
• Base excision repair
• Telomerase
• Telomeres
• oxidative stress

• DNA glycosylases
• DNA repair
• epigenetic markers
• neurological disorders
• oxidative DNA lesions

• Animals
• Brain/physiology
• Brain Injuries/enzymology
• DNA Glycosylases/metabolism
• DNA Repair
• Epigenesis, Genetic
• Humans
• Neurodegenerative Diseases/enzymology
• Oxidative Stress
• Regeneration

• 90421400 The Research Council of Norway

• DNA repair
• Huntington’s disease
• mismatch repair
• myotonic dystrophy 1
• trinucleotide repeat instability

• anti-cancer
• cancer
• pro-tumor
• reactive oxygen species
• self-adaption system
• therapy

MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor. In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs, inducing G:C to T:A transversions. MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production. MUTYH mutations have been linked to MUTYH associated polyposis syndrome (MAP), an autosomal recessive disorder characterized by multiple colorectal adenomas. MAP patients show a greatly increased lifetime risk for gastrointestinal cancers. The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases. This review evaluates the role of MUTYH, focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer. This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis. Furthermore, we describe the association between MUTYH single nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets. Considering the multiple functions and interactions of MUTYH protein, its involvement in pathologies based on oxidative stress damage could be hypothesized. Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined, the risk for malignancies of the duodenum, ovary, and bladder is also increased as well as the onset of benign and malignant endocrine tumors. The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells. Furthermore, some MUTYH SNPs have been associated with lung, hepatocellular and cervical cancer risk. An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis, including neurological and ocular diseases. Finally, it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.

• MUTYH
• Polyposis
• Colorectal cancer
• Base excision repair
• Mutations
• Single nucleotide polymorphism

• Bisphenol A
• Bisphenol AF
• Bisphenol F
• DNA bases lesions
• PBMCs

• Benzhydryl Compounds/toxicity
• Cell Survival/drug effects
• Cells, Cultured
• Comet Assay
• DNA Damage
• Dose-Response Relationship, Drug
• Humans
• Leukocytes, Mononuclear/drug effects
• Leukocytes, Mononuclear/pathology
• Mutagens/toxicity
• Oxidation-Reduction
• Oxidative Stress/drug effects
• Oxidative Stress/genetics
• Phenols/toxicity
• Sulfones/toxicity

• E/I balance
• FMR1
• Fragile X Syndrome
• autism spectrum disorders
• behavior and cognition
• microsatellite instability
• mouse model
• primates

• U42 OD012210 NIH HHS

Oxidative DNA damage and base excision repair (BER) play important roles in modulating trinucleotide repeat (TNR) instability that is associated with human neurodegenerative diseases and cancer. We have reported that BER of base lesions can lead to TNR instability. However, it is unknown if modifications of the sugar in an abasic lesion modulate TNR instability. In this study, we characterized the effects of the oxidized sugar, 5’-(2-phosphoryl-1,4-dioxobutane)(DOB) in CAG repeat tracts on the activities of key BER enzymes, as well as on repeat instability. We found that DOB crosslinked with DNA polymerase β and inhibited its synthesis activity in CAG repeat tracts. Surprisingly, we found that DOB also formed crosslinks with DNA ligase I and inhibited its ligation activity, thereby reducing the efficiency of BER. This subsequently resulted in the accumulation of DNA strand breaks in a CAG repeat tract. Our study provides important new insights into the adverse effects of an oxidized abasic lesion on BER and suggests a potential alternate repair pathway through which an oxidized abasic lesion may modulate TNR instability.

CAG/CTG trinucleotide repeat expansions cause several degenerative neurological and muscular diseases. Koch et al. show that the chromatin remodeling...

CAG/CTG trinucleotide repeats are unstable sequences that are difficult to replicate, repair, and transcribe due to their structure-forming nature. CAG repeats strongly position nucleosomes; however, little is known about the chromatin remodeling needed to prevent repeat instability. In a Saccharomyces cerevisiae model system with CAG repeats carried on a YAC, we discovered that the chromatin remodeler Isw1 is required to prevent CAG repeat expansions during transcription. CAG repeat expansions in the absence of Isw1 were dependent on both transcription-coupled repair (TCR) and base-excision repair (BER). Furthermore, isw1∆ mutants are sensitive to methyl methanesulfonate (MMS) and exhibit synergistic MMS sensitivity when combined with BER or TCR pathway mutants. We conclude that CAG expansions in the isw1∆ mutant occur during a transcription-coupled excision repair process that involves both TCR and BER pathways. We observed increased RNA polymerase II (RNAPII) occupancy at the CAG repeat when transcription of the repeat was induced, but RNAPII binding did not change in isw1∆ mutants, ruling out a role for Isw1 remodeling in RNAPII progression. However, nucleosome occupancy over a transcribed CAG tract was altered in isw1∆ mutants. Based on the known role of Isw1 in the reestablishment of nucleosomal spacing after transcription, we suggest that a defect in this function allows DNA structures to form within repetitive DNA tracts, resulting in inappropriate excision repair and repeat-length changes. These results establish a new function for Isw1 in directly maintaining the chromatin structure at the CAG repeat, thereby limiting expansions that can occur during transcription-coupled excision repair.

• CAG repeat expansion
• ISWI chromatin remodeler
• base excision repair
• transcription-coupled repair

The genetic basis of X-Linked dystonia-parkinsonism (XDP) has been difficult to unravel, in part because all patients inherit the same haplotype of seven sequence variants, none of which has ever been identified in control individuals. This study revealed that one of the haplotype markers, a retrotransposon insertion within an intron of TAF1, has a variable number of hexameric repeats among affected individuals with an increase in repeat number strongly correlated with earlier age at disease onset. These data support a contributing role for this sequence in disease pathogenesis while further suggesting that XDP may be part of a growing list of neurodegenerative disorders associated with unstable repeat expansions.

X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1. This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding protein–associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)_n. The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression.

• DYT3
• Parkinson’s disease
• TAF1
• XDP
• dystonia

• 8-oxo-G
• 8-oxoG
• Cancer
• DNA polymerase switch
• DNA polymerase β
• DNA polymerase δ
• DNA polymerase λ
• MUTYH
• OGG1
• Oxidative stress

• DNA Repair/genetics
• Genome-Wide Association Study
• Humans
• Huntingtin Protein/genetics
• Huntington Disease/genetics
• Trinucleotide Repeat Expansion/genetics

• MR/L02053X/1 Medical Research Council
• MR/L010305/1 Medical Research Council
• G108/638 Medical Research Council
• 200181/Z/15/Z Wellcome Trust
• MR/J004758/1 Medical Research Council
• MC_PC_14108 Medical Research Council
• G0802760 Medical Research Council
• G1001253 Medical Research Council
• MR/L012936/1 Medical Research Council

• Huntington’s Disease
• Oxidative stress
• redox changes
• transcriptional processes

• Humans
• Huntington Disease/physiopathology
• Oxidative Stress/physiology

• P01 AG014930 NIA NIH HHS

• Animals
• Disease Models, Animal
• Endoplasmic Reticulum/genetics
• Endoplasmic Reticulum/pathology
• Humans
• Huntingtin Protein/genetics
• Huntington Disease/genetics
• Huntington Disease/metabolism
• Huntington Disease/pathology
• Mice
• Mutation
• Oxidative Stress/genetics
• Phosphorylation/genetics
• Protein Domains
• Reactive Oxygen Species/metabolism

• MOP-119391 CIHR