EXO1
Exonuclease 1 (EC 3.1.-.-) (hExo1) (Exonuclease I) (hExoI) [EXOI] [HEX1]
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Evidence indicates that the age-related neuropathological mechanisms associated with DNA repair genes may contribute to cognitive aging and Alzheimer's disease. In this study, we hypothesize that single nucleotide polymorphisms (SNPs) within 155 DNA repair genes may be linked to cognitive aging independently and/or through complex interactions in an older Taiwanese population. A total of 3,730 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) was administered to all subjects, and MMSE scores were used to measure cognitive functions. Our data showed that out of 1,652 SNPs, the rs1776181 (P = 1.47 × 10 ), rs1776177 (P = 8.42 × 10 ), rs1635510 (P = 7.97 × 10 ), and rs2526698 (P = 7.06 × 10 ) SNPs in the EXO1 gene were associated with cognitive aging. The association with these SNP remained significant after performing Bonferroni correction. Additionally, we found that interactions between the EXO1 and RAD51C genes influenced cognitive aging (P = 0.002). Finally, we pinpointed the influence of interactions between EXO1 and physical activity (P < 0.001) as well as between DCLRE1C and physical activity (P < 0.001). Our study indicated that DNA repair genes may contribute to susceptibility in cognitive aging independently as well as through gene-gene and gene-physical interactions.
MeSH Terms
- Aged
- Cognitive Aging
- DNA Repair
- DNA Repair Enzymes
- Exodeoxyribonucleases
- Female
- Genotype
- Humans
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Taiwan
Keywords
- Alzheimer’s diseases
- Cognitive aging
- Cognitive impairment
- Gene-gene interactions
- Neurodegeneration
- Single nucleotide polymorphisms
Exonuclease 1 (EXO1) is a multifunctional 5' → 3' exonuclease and a DNA structure-specific DNA endonuclease. EXO1 plays roles in DNA replication, DNA mismatch repair (MMR) and DNA double-stranded break repair (DSBR) in lower and higher eukaryotes and contributes to meiosis, immunoglobulin maturation, and micro-mediated end-joining in higher eukaryotes. In human cells, EXO1 is also thought to play a role in telomere maintenance. Mutations in the human EXO1 gene correlate with increased susceptibility to some cancers. This review summarizes recent studies on the enzymatic functions and biological roles of EXO1, its possible protective role against cancer and aging, and regulation of EXO1 by posttranslational modification.
MeSH Terms
- Aging
- Animals
- DNA Breaks
- DNA Repair
- Exodeoxyribonucleases
- Humans
- Meiosis
- Mutation
- Neoplasms
- Protein Processing, Post-Translational
Keywords
- Aging
- DNA repair
- EXO1
- cancer
- double-strand break repair
- mismatch repair
- post-translational modification
- telomere maintenance
Evidence from model organisms suggests that the insulin/IGF-1 signaling pathway has an important, evolutionarily conserved influence over rate of aging and thus longevity. In humans, the FOXO3 gene is the only widely replicated insulin/IGF-1 signaling pathway gene associated with longevity across multiple populations. Therefore, we conducted a nested case-control study of other insulin/IGF-1 signaling genes and longevity, utilizing a large, homogeneous, long-lived population of American men of Japanese ancestry, well characterized for aging phenotypes. Genotyping was performed of single nucleotide polymorphisms, tagging most of the genetic variation across several genes in the insulin/IGF-1 signaling pathway or related gene networks that may be influenced by FOXO3, namely, ATF4, CBL, CDKN2, EXO1, and JUN. Two initial, marginal associations with longevity did not remain significant after correction for multiple comparisons, nor were they correlated with aging-related phenotypes.
MeSH Terms
- Activating Transcription Factor 4
- Aged, 80 and over
- Aging
- Asian Americans
- Case-Control Studies
- Cohort Studies
- DNA Repair Enzymes
- Exodeoxyribonucleases
- Forkhead Box Protein O3
- Forkhead Transcription Factors
- Gene Frequency
- Genes, jun
- Genes, p16
- Genetic Variation
- Genotype
- Humans
- Insulin
- Insulin Resistance
- Insulin-Like Growth Factor I
- Japan
- Longevity
- Longitudinal Studies
- Male
- Polymorphism, Genetic
- Polymorphism, Single Nucleotide
- Proto-Oncogene Proteins c-cbl
- Signal Transduction
Keywords
- Human.
- Insulin signaling genes
- Longevity
- Molecular genetics
Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the C allele of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. The C allele leads to the loss of a binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression. Thus, we have detected a hitherto undescribed role for E47 as a negative regulator of EXO1 transcription and a genetic variant in the EXO1 promoter that counteracts the E47-mediated repression of the gene. Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene.
MeSH Terms
- Aged
- Aged, 80 and over
- Binding Sites
- Case-Control Studies
- DNA Repair Enzymes
- Exodeoxyribonucleases
- Female
- Gene Expression Regulation, Neoplastic
- Gene Frequency
- Germany
- HeLa Cells
- Humans
- Jurkat Cells
- Logistic Models
- Longevity
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- RNA, Messenger
- Sex Factors
- TCF Transcription Factors
- Transcription Factor 7-Like 1 Protein
- Transfection
- Up-Regulation
Exonuclease-1 (EXO1) mediates checkpoint induction in response to telomere dysfunction in yeast, but it is unknown whether EXO1 has similar functions in mammalian cells. Here we show that deletion of the nuclease domain of Exo1 reduces accumulation of DNA damage and DNA damage signal induction in telomere-dysfunctional mice. Exo1 deletion improved organ maintenance and lifespan of telomere-dysfunctional mice but did not increase chromosomal instability or cancer formation. Deletion of Exo1 also ameliorated the induction of DNA damage checkpoints in response to gamma-irradiation and conferred cellular resistance to 6-thioguanine-induced DNA damage. Exo1 deletion impaired upstream induction of DNA damage responses by reducing ssDNA formation and the recruitment of Replication Protein A (RPA) and ATR at DNA breaks. Together, these studies provide evidence that EXO1 contributes to DNA damage signal induction in mammalian cells, and deletion of Exo1 can prolong survival in the context of telomere dysfunction.
MeSH Terms
- Animals
- Apoptosis
- Ataxia Telangiectasia Mutated Proteins
- Cell Cycle Proteins
- Cell Proliferation
- Chromosomal Instability
- DNA Damage
- DNA, Single-Stranded
- Exodeoxyribonucleases
- Gamma Rays
- Gene Deletion
- Gene Fusion
- Genotype
- Intestinal Mucosa
- Longevity
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mutagens
- Phenotype
- Protein-Serine-Threonine Kinases
- RNA
- Replication Protein A
- Signal Transduction
- Telomerase
- Telomere
- Thioguanine
Telomerase-defective budding yeast cells escape senescence by using homologous recombination to amplify telomeric or subtelomeric structures. Similarly, human cells that enter senescence can use homologous recombination for telomere maintenance, when telomerase cannot be activated. Although recombination proteins required to generate telomerase-independent survivors have been intensively studied, little is known about the nucleases that generate the substrates for recombination. Here we demonstrate that the Exo1 exonuclease is an initiator of the recombination process that allows cells to escape senescence and become immortal in the absence of telomerase. We show that EXO1 is important for generating type I survivors in yku70delta mre11delta cells and type II survivors in tlc1delta cells. Moreover, in tlc1delta cells, EXO1 seems to contribute to the senescence process itself.
MeSH Terms
- Aging
- Blotting, Southern
- Exodeoxyribonucleases
- Genotype
- Models, Genetic
- Recombination, Genetic
- Saccharomycetales
- Telomere