ATM-dependent phosphorylation of SNEVhPrp19/hPso4 is involved in extending cellular life span and suppression of apoptosis

Aging (Albany NY). 2012 Apr;4(4):290-304. doi: 10.18632/aging.100452.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Ataxia Telangiectasia Mutated Proteins
  • Blotting, Western
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics*
  • DNA Breaks, Double-Stranded*
  • DNA Repair / genetics*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • HeLa Cells
  • Humans
  • Oxidative Stress / genetics*
  • Phosphorylation / genetics*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics*
  • RNA Precursors / chemistry
  • RNA Precursors / genetics
  • Sequence Analysis, Protein
  • Serine / genetics
  • Serine / metabolism
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • RNA Precursors
  • Tumor Suppressor Proteins
  • Serine
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases