Abstract
Defective DNA repair is widely acknowledged to negatively impact on healthy aging, since mutations in DNA repair factors lead to accelerated and premature aging. However, the opposite, namely if improved DNA repair will also increase the life or health span is less clear, and only few studies have tested if overexpression of DNA repair factors modulates life and health span in cells or organisms. Recently, we identified and characterized SNEVhPrp19/hPso4, a protein that plays a role in DNA repair and pre-mRNA splicing, and observed a doubling of the replicative life span upon ectopic overexpression, accompanied by lower basal DNA damage and apoptosis levels as well as an increased resistance to oxidative stress. Here we find that SNEVhPrp19/hPso4 is phosphorylated at S149 in an ataxia telangiectasia mutated protein (ATM)-dependent manner in response to oxidative stress and DNA double strand break inducing agents. By overexpressing wild-type SNEVhPrp19/hPso4 and a phosphorylation-deficient point-mutant, we found that S149 phosphorylation is necessary for mediating the resistance to apoptosis upon oxidative stress and is partially necessary for elongating the cellular life span. Therefore, ATM dependent phosphorylation of SNEVhPrp19/hPso4 upon DNA damage or oxidative stress might represent a novel axis capable of modulating cellular life span.
Highlights
Accumulation of DNA damage, if not repaired, can lead to premature aging, as indicated by several inherited diseases caused by mutations of DNA damage response factors that show features of premature aging [1], [2]
We find that SNEVhPrp19/hPso4 is phosphorylated at S149 in an ataxia telangiectasia mutated protein (ATM)‐dependent manner in response to oxidative stress and DNA double strand break inducing agents
Oxidative stress induces an additional SNEV protein band in Western blotting From previous results we know that SNEV expression is induced upon oxidative and DNA double strand breaks (DSB) damage [23, 26]
Summary
Accumulation of DNA damage, if not repaired, can lead to premature aging, as indicated by several inherited diseases caused by mutations of DNA damage response factors that show features of premature aging [1], [2]. One of the proteins orchestrating DNA damage response is ATM (ataxia telangiectasia mutated), which plays a central and multiple role in the cellular stress response by monitoring and maintaining DNA integrity (reviewed by [4]). These crucial functions are mirrored by the disorder caused by its mutations, Ataxia telangiectasia (A-T), which is classified as a segmental progeroid syndrome [5] and includes symptoms like cerebellar degeneration, immunodeficency, genomic instability, thymic and gonadal atrophy and cancer predisposition [6].
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