期刊
CELL CYCLE
卷 14, 期 2, 页码 269-276出版社
LANDES BIOSCIENCE
DOI: 10.4161/15384101.2014.980641
关键词
aging; base excision repair; mono-ADP-ribosylation; PARP1; SIRT6; SIRTUIN
类别
资金
- National Basic Research Program of China (973 Program) [2013CB967600, 2015CB964800]
- National Science Foundation of China [31371396]
- Shanghai Pujiang Program [13PJ1408300]
- 1000 Youth Talents Program
- Open Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [SKLNMKF201404]
- Cultural Program for Outstanding Young Talents in Tongji University, the National Science Foundation for Post-doctoral Scientists of China [2014M551446]
In principle, a decline in base excision repair (BER) efficiency with age should lead to genomic instability and ultimately contribute to the onset of the aging phenotype. Although multiple studies have indicated a negative link between aging and BER, the change of BER efficiency with age in humans has not been systematically analyzed. Here, with foreskin fibroblasts isolated from 19 donors between 20 and 64 y of age, we report a significant decline of BER efficiency with age using a newly developed GFP reactivation assay. We further observed a very strong negative correlation between age and the expression levels of SIRT6, a factor which is known to maintain genomic integrity by improving DNA double strand break (DSB) repair. Our mechanistic study suggests that, similar to the regulatory role that SIRT6 plays in DNA DSB repair, SIRT6 regulates BER in a PARP1-depdendent manner. Moreover, overexpression of SIRT6 rescues the decline of BER in aged fibroblasts. In summary, our results uncovered the regulatory mechanisms of BER by SIRT6, suggesting that SIRT6 reactivation in aging tissues may help delay the process of aging through improving BER.
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