title: SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner.
abstract: 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.
authors.affiliation: a Department of Clinical Laboratory Medicine; Shanghai Tenth People's Hospital; School of Life Sciences and Technology; Tongji University ; Shanghai , China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Xu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: Du
authors.initials: D
authors.lastname: Meng
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: Van Meter
authors.forename: Andrei
authors.initials: A
authors.lastname: Seluanov
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Mao
mesh_terms: D000328:Adult; D000375:Aging; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D052816:Foreskin / Q000166:cytology; D042822:Genomic Instability; D006801:Humans; D008027:Light; D008297:Male; D008875:Middle Aged; D010616:Phenanthrenes / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; D011065:Poly(ADP-ribose) Polymerases; C516592:SIRT6 protein, human; D037761:Sirtuins
keywords: PARP1; SIRT6; SIRTUIN; aging; base excision repair; mono-ADP-ribosylation