ATM-dependent phosphorylation of SNEVhPrp19/hPso4 is involved in extending cellular life span and suppression of apoptosis.
ATM-dependent phosphorylation of SNEVhPrp19/hPso4 is involved in extending cellular life span and suppression of apoptosis.
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DOI：
10.18632/aging.100452
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
Grillari J
中科院分区：
文献类型：
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作者：
Dellago H;Khan A;Nussbacher M;Gstraunthaler A;Lämmermann I;Schosserer M;Mück C;Anrather D;Scheffold A;Ammerer G;Jansen-Dürr P;Rudolph KL;Voglauer-Grillari R;Grillari J
DNA修复缺陷被广泛认为对健康衰老有负面影响，因为DNA修复因子的突变会导致加速和过早衰老。然而，相反，即改善的DNA修复是否也会增加寿命或健康寿命尚不清楚，只有很少的研究测试过DNA修复因子的过表达是否会调节细胞或生物体的寿命和健康寿命。最近，我们确定并表征了SNEVhPrp 19/hPso 4，一种在DNA修复和前mRNA剪接中起作用的蛋白质，并观察到异位过表达后复制寿命延长一倍，伴随着较低的基础DNA损伤和凋亡水平以及对氧化应激的抵抗力增加。我们发现SNEVhPrp 19/hPso 4在氧化应激和DNA双链断裂诱导剂的作用下，以共济失调毛细血管扩张突变蛋白（ATM）依赖的方式在S149处磷酸化。通过过量表达野生型SNEVhPrp 19/hPso 4和磷酸化缺陷的点突变体，我们发现S149磷酸化是介导氧化应激后抗凋亡所必需的，并且是延长细胞寿命所必需的部分。因此，ATM依赖的SNEVhPrp 19/hPso 4在DNA损伤或氧化应激时的磷酸化可能代表了能够调节细胞寿命的新轴。
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.