A functional EXO1 promoter variant is associated with prolonged life expectancy in centenarians.
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.
Nebel
Almut
A
Institute of Clinical Molecular Biology, the Christian-Albrechts-University, Kiel, Germany.
Flachsbart
Friederike
F
Till
Andreas
A
Caliebe
Amke
A
Blanché
Hélène
H
Arlt
Alexander
A
Häsler
Robert
R
Jacobs
Gunnar
G
Kleindorp
Rabea
R
Franke
Andre
A
Shen
Binghui
B
Nikolaus
Susanna
S
Krawczak
Michael
M
Rosenstiel
Philip
P
Schreiber
Stefan
S
D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D016022:Case-Control Studies; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005858:Germany; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D016015:Logistic Models; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D051820:TCF Transcription Factors / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein; D014162:Transfection; D015854:Up-Regulation
D012333:RNA, Messenger; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; D058125:Transcription Factor 7-Like 1 Protein; C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes