Cloning and characterization of mammalian 8-hydroxyguanine-specific DNA glycosylase/apurinic, apyrimidinic lyase, a functional mutM homologue

• Published in: Cancer research (Chicago, Ill.) Ill.), 1997-06, Vol.57 (11), p.2151-2156
• Main Authors: ABURATANI, H, HIPPO, Y, FUKASAWA, K, YOSHINARI, T, INOUE, H, OHTSUKA, E, NISHIMURA, S, ISHIDA, T, TAKASHIMA, R, MATSUBA, C, KODAMA, T, TAKAO, M, YASUI, A, YAMAMOTO, K, ASANO, M
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Amino Acid Sequence; Animals; Antisense Elements (Genetics); Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - genetics; Chromosome Mapping; Cloning, Molecular; Deoxyribonuclease IV (Phage T4-Induced); DNA Glycosylases; DNA-(Apurinic or Apyrimidinic Site) Lyase; DNA-Formamidopyrimidine Glycosylase; Escherichia coli Proteins; Exons; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Guanine - analogs & derivatives; Guanine - metabolism; Humans; Lyases - genetics; Lyases - metabolism; Mice; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Mutagenesis. Repair; N-Glycosyl Hydrolases - genetics; Sequence Homology, Amino Acid
• ISSN: 0008-5472; 1538-7445

8-Hydroxyguanine (8-OH-G) is one of the major DNA oxidation products implicated in mutagenesis induced by oxygen radical-forming agents, including ionizing radiation. It is also believed to be involved in spontaneous mutation induced by metabolically produced oxygen radicals. A mammalian homologue of 8-OH-G glycosylase/apurinic, apyrimidinic lyase (mutM homologue, MMH) has been identified in the EST database (for expressed sequence tags) through a homology search with yeast OGG1 protein. The human MMH protein (hMMH), 34% identical to the yeast OGG1 protein, is a member of the DNA repair protein superfamily. The hMMH gene was composed of seven exons, with the alternate last exon, exon 8, producing three major alternative splicing isoforms, because splicing of the sixth intron was optional. The hMMH protein expressed in Escherichia coli revealed the glycosylase activity and apurinic, apyrimidinic lyase activity on duplex DNA containing 8-OH-G. The hMMH protein can rescue a spontaneous mutator strain of E. coli lacking mutM and mutY. By the introduction of recombinant hMMH, the rate of mutation, the formation of rifampicin-resistant revertants, was reduced by 4-7 fold. Genomic structure analysis showed that 3' exons of the hMMH gene are transcribed on the antisense strand of the calcium-dependent calmodulin kinase 1 gene.