Apurinic/apyrimidinic endonuclease 1, p53, and thioredoxin are linked in control of aging inC. elegans

Abstract

SummaryDeletions in mitochondrial DNA (mtDNA) accumulate during aging. Expression of the Caenorhabditis elegans apurinic ⁄ apyrimidinic endonuclease 1 (APE1) ortholog exo-3, involved in DNA repair, is reduced by 45% (P < 0.05) during aging of C. elegans. Suppression of exo-3 by treatment with RNAi resulted in a threefold increase in mtDNA deletions (P < 0.05), twofold enhanced generation of reactive oxygen species (ROS) (P < 0.01), distortion of the structural integrity of the nervous system, reduction of head motility by 43% (P < 0.01) and whole animal motility by 38% (P < 0.05). Suppression of exo-3 significantly reduced life span: mean life span decreased from 18.5 ± 0.4 to 15.4 ± 0.1 days (P < 0.001) and maximum life span from 25.9 ± 0.4 to 23.2 ± 0.1 days (P = 0.001). Additional treatment of exo-3-suppressed animals with a mitochondrial uncoupler decreased ROS levels, reduced neuronal damage, and increased motility and life span. Additional suppression of the C. elegans p53 ortholog cep-1 in exo-3 RNAi-treated animals similarly decreased ROS levels, preserved neuronal integrity, and increased motility and life span. In wild-type animals, suppression of cep-1, involved in downregulation of exo-3, increased expression of exo-3 without a significant effect on ROS levels, preserved neuronal integrity, and increased motility and life span. Suppression of the C. elegans thioredoxin orthologs trx-1 and trx-2, involved in the redox chaperone activity of exo-3, overrides the protective effect of cep-1 RNAi treatment on neuronal integrity, neuronal function, mean and maximum life span. These results show that APE1 ⁄ EXO-3, p53 ⁄ CEP-1, and thioredoxin affect each other and that these interactions determine aging as well as neuronal structure and function.

daf-16/FOXO and glod-4/glyoxalase-1 are required for the life-prolonging effect of human insulin under high glucose conditions in Caenorhabditis elegans

“…Glyoxalase-1 is the major enzyme detoxifying methylglyoxal (MG), a precursor in AGE formation [8,10]. Increased accumulation of AGEs in turn further reduces glyoxalase-1 activity, induces ROS formation in a vicious feed-forward loop and ultimately contributes to reduced neuronal function and lifespan [11][12][13][14][15]. It has been shown that overexpression of glyoxalase-1 prolongs lifespan, establishing a causal connection between lifespan and glyoxalase-1 activity [16].…”

Control of Trx1 redox state modulates protection against methyl methanesulfonate-induced DNA damage via stabilization of p21

“…Collectively, it is possible that Trx1 may exert a protective role against DNA damage through inhibiting translation by regulating phosphorylation of 4E-BP1 to save energy, possibly through cell cycle arrest by affecting p21 stability and allowing more time for DNA repair, thus eventually reducing MMS-induced cell death and enhancing cell survival. Indeed, protection of Trx1 against MMS-induced DNA damage could have been involved in DNA repair as redox signalling has been shown to affect APE1/Ref1 function, an apurinic/apyrimidinic endonuclease in the DNA base excision repair pathway (38,39), and APE1/Ref1 was shown to regulate the p53/p21 system (37,40). In addition, it was reported that the heat-stable cytosolic factor that promotes glucocorticoid receptor binding to DNA after MMS treatment is neither thioredoxin nor ribonuclease (41), suggesting that Trx1-mediated protection against MMS-induced DNA damage might be specific through certain cellular factors.…”

FUdR extends the lifespan of the short-lived AP endonuclease mutant in <i>Caenorhabditis elegans</i> in a fertility-dependent manner

“…We previously reported that deletion of the exo-3 gene, but not the apn-1 gene, results in decreased lifespan in the absence of FUdR in a ung-1-dependent manner (Kato et al, 2015). EXO-3 and APN-1 are AP endonucleases (Shatilla et al, 2005;Schlotterer et al, 2010;Zakaria et al, 2010;Yang et al, 2012), and UNG-1 is a uracil DNA glycosylase in C. elegans (Nakamura et al, 2008). In this study, we measured the lifespan of the exo-3 mutant in the presence of FUdR, and found that FUdR extended the lifespan of the mutant.…”