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A functional EXO1 promoter variant is associated with prolonged life expectancy in centenarians
- Source :
- Mechanisms of ageing and development. 130(10)
- Publication Year :
- 2008
-
Abstract
- 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. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
- Subjects :
- Male
Aging
Candidate gene
media_common.quotation_subject
Longevity
Transcription Factor 7-Like 1 Protein
Single-nucleotide polymorphism
Biology
Transfection
Polymorphism, Single Nucleotide
Exonuclease 1
Jurkat Cells
Sex Factors
Gene Frequency
Germany
Humans
RNA, Messenger
Allele
Promoter Regions, Genetic
Transcription factor
Gene
Allele frequency
media_common
Aged
Genetics
Aged, 80 and over
Binding Sites
Middle Aged
Up-Regulation
Gene Expression Regulation, Neoplastic
DNA Repair Enzymes
Exodeoxyribonucleases
Logistic Models
Case-Control Studies
Female
TCF Transcription Factors
Developmental Biology
HeLa Cells
Subjects
Details
- ISSN :
- 18726216
- Volume :
- 130
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Mechanisms of ageing and development
- Accession number :
- edsair.doi.dedup.....8f75dd3d136b6350c5c38b3f572551a7