Differential regulation of expression of the mammalian DNA repair genes by growth stimulation.
During DNA replication, DNA becomes more vulnerable to certain DNA damages. DNA repair genes involved in repair of the damages may be induced by growth stimulation. However, regulation of DNA repair genes by growth stimulation has not been analysed in detail. In this report, we analysed the regulation of expression of mammalian MSH2, MSH3 and MLH1 genes involved in mismatch repair, and Rad51 and Rad50 genes involved in homologous recombination repair, in relation to cell growth. Unexpectedly, we found a clear difference in regulation of these repair gene expression by growth stimulation even in the same repair system. The expression of MSH2, MLH1 and Rad51 genes was clearly growth regulated, whereas MSH3 and Rad50 genes were constitutively expressed, suggesting differential requirement of the repair gene products for cell proliferation. MSH3 gene is located in a bidirectionally divergent manner with DHFR gene that is regulated by growth stimulation, indicating that bidirectionally divergent promoters are not necessarily coordinately regulated. Promoter analysis showed that the growth-regulated expression of MLH1 and Rad51 genes was mainly mediated by E2F that plays crucial roles in regulation of DNA replication, suggesting close relation between some of the repair genes and DNA replication.
Human Gene Sciences Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Ritsuko
R
Iwanaga
Hideyuki
H
Komori
Kiyoshi
K
Ohtani
D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects*; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase; D014157:Transcription Factors / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006133:Growth Substances; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes