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Journal of Biochemistry Advance Access originally published online on July 31, 2008
Journal of Biochemistry 2008 144(4):523-529; doi:10.1093/jb/mvn097
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© 2008 The Japanese Biochemical Society.

Down-regulation of Asymmetric Arginine Methylation During Replicative and H2O2-induced Premature Senescence in WI-38 Human Diploid Fibroblasts

Yongchul Lim1, Eunil Lee2,*, Joohyun Lee3, Sangnam Oh1 and Sangduk Kim4

1Department of Cellular and Developmental Biology, Division of Brain Korea 21 Program for Biomedical Sciences; 2Department of Preventive Medicine; 3Postgraduate Studies of Public Health, Graduate School; and 4Graduate School of Biomedical Sciences, Division of Brain Korea 21, Korea University, College of Medicine, Seoul 136-705, Korea

*To whom correspondence should be addressed. Tel: +82-2-920-6170, Fax: +82-2-927-7220, E-mail: eunil{at}korea.ac.kr

Received July 14, 2008; Accepted July 20, 2008


  Abstract

Protein arginine methylation is one of the post-translational modifications which yield monomethyl and dimethyl (asymmetric or symmetric) arginines in proteins. In the present study, we investigated the status of protein arginine methylation during human diploid fibroblast senescence. When the expression of protein arginine methyltransferases (PRMTs), namely PRMT1, PRMT4, PRMT5 and PRMT6 was examined, a significant reduction was found in replicatively senescent cells as well as their catalytic activities against histone mixtures compared with the young cells. Furthermore, when the endogenous level of arginine-dimethylated proteins was determined, asymmetric modification (the product of type I PRMTs including PRMT1, PRMT4 and PRMT6) was markedly down-regulated. In contrast, both up- and down-regulations of symmetrically arginine-methylated proteins (the product of type II PRMTs including PRMT5) during replicative senescence were found. Furthermore, when young fibroblasts were induced to premature senescence by sub-cytotoxic H2O2 treatment, results similar to replicative senescence were obtained. Finally, we found that SV40-mediated immortalized WI-38 and HeLa cell lines maintained a higher level of asymmetrically modified proteins as well as type I PRMTs than young fibroblasts. These results suggest that the maintenance of asymmetric modification in the expressed target proteins of type I PRMTs might be critical for cellular proliferation.

Key Words: dimethylarginines, human diploid fibroblasts, H2O2-induced premature senescence, protein arginine methyltransferases, replicative senescence

Abbreviations: aDMA, asymmetric NG, NG-dimethyl arginine; CPDL, cumulative population doubling level; HDFs, human diploid fibroblasts; MMA, NG-monomethyl-arginine; PRMT, protein arginine methyltransferase; RS, replicative senescence; SA-β-gal, senescence-associated β-galactosidase; sDMA, symmetric NG,N'G-dimethyl arginine


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