Evidence of the modulation of mRNA splicing fidelity in humans by oxidative stress and p53.
The majority of human genes generate mRNA splice variants and while there is little doubt that alternative splicing is an important biological phenomenon, it has also become apparent that some splice variants are associated with disease. To elucidate the molecular mechanisms responsible for generating aberrant splice variants, we have investigated alternative splicing of the human genes HPRT and POLB following oxidative stress in different genetic backgrounds. Our study revealed that splicing fidelity is sensitive to oxidative stress. Following treatment of cells with H2O2, the overall frequency of aberrant, unproductive splice variants increased in both loci. At least in POLB, splicing fidelity is p53 dependent. In the absence of p53, the frequency of POLB splice variants is elevated but oxidative stress does not further increase the frequency of splice variants. Our data indicate that mis-splicing following oxidative stress represents a novel and significant genotoxic outcome and that it is not simply DNA lesions induced by oxidative stress that lead to mis-splicing but changes in the alternative splicing machinery itself.
Disher
Kim
K
Department of Biological Sciences, Brock University, 500 Glenridge Avenue, St. Catharines, ON L2S 3A1, Canada.
Skandalis
Adonis
A
D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D019951:DNA Polymerase beta / Q000235:genetics*; D005091:Exons / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D007041:Hypoxanthine Phosphoribosyltransferase; D019951:DNA Polymerase beta