A functional single nucleotide polymorphism in promoter of ATM is associated with longevity.
Although the 'ataxia telangiectasia mutated' (ATM) gene plays an important role in physiological processes, such as sensing DNA damage, reducing oxidative stress and protecting telomeres length, little information about ATM and longevity is available. Therefore, we aim to examine the association between genetic variants in promoter of ATM and longevity in Chinese Nonagenarians/Centenarians. Genotyping was performed in 789 long-lived individuals (LLIs) and 886 ethnically matched control subjects. A single nucleotide polymorphism (SNP, rs189037) in the promoter region of ATM gene was identified, and significant association between CT genotype and longevity was observed. Meanwhile, the SNP was able to affect expression of ATM mRNA by differentially binding to AP-2α. The CC genotype strongly bound to AP-2α, and the TT genotype showed less binding affinity to AP-2α. The AP-2α strongly repressed the reporter expression in the CC genotype and showed less repression of the TT genotype driving expression in vitro assay. Accordingly, TT genotype individuals had highest ATM mRNA expression, CT genotype individuals had moderate ATM mRNA expression, and the CC genotype individuals had the lowest ATM mRNA.
Chen
Tie
T
Laboratory of Stem Cell Biology and Department of Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Dong
Birong
B
Lu
Zhenchan
Z
Tian
Baochun
B
Zhang
Jian
J
Zhou
Jianlin
J
Wu
Hongmei
H
Zhang
Yanling
Y
Wu
Jinhui
J
Lin
Ping
P
Zhang
Jie
J
Xu
Hong
H
Mo
Xianming
X
D000369:Aged, 80 and over; D044466:Asian People; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics*; D002681:China; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005838:Genotype; D006801:Humans; D008136:Longevity / Q000502:physiology*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050656:Transcription Factor AP-2; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases