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Gene Review

Mutyh  -  mutY homolog (E. coli)

Mus musculus

Synonyms: 5730495A01Rik, A/G-specific adenine DNA glycosylase, MutY homolog, Mutyha, Mutyhalpha, ...
 
 
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Disease relevance of Mutyh

  • Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas [1].
  • Though in many respects the catalytic behavior of mMYH is similar to E. coli MutY, the subtle differences may translate into differences in their in vivo functions [2].
  • We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thus providing experimental evidence for the association between biallelic germ-line MUTYH mutations and a recessive form of human hereditary colorectal adenoma and carcinoma [3].
 

High impact information on Mutyh

  • Accumulation of the oxidative base lesion 8-hydroxyguanine in DNA of tumor-prone mice defective in both the Myh and Ogg1 DNA glycosylases [4].
  • In Myh(-/-) mice, there was no time-dependent accumulation of DNA 8-hydroxyguanine in brain, small intestine, lung, spleen, or kidney [4].
  • Whereas mice heterozygous for mutant Apc develop intestinal tumors, mice homozygous for mutant Myh do not show increased tumor susceptibility [5].
  • Tumors from Apc(Min/+)/Myh(+/-) mice harbored neither somatic mutations nor allelic loss at Myh [5].
  • Our results provide regional assignments of Myh and Trp53-1 to chromosome bands B2----C, and of Erbb to bands A1----A4 [6].
 

Chemical compound and disease context of Mutyh

  • Surprisingly, the intrinsic rates of adenine removal from both OG:A and G:A substrates by mMYH are diminished ( approximately 10-fold) compared to E. coli MutY [2].
 

Biological context of Mutyh

  • There are three types of mouse Mutyh mRNAs (type a, b and c) generated by alternative splicing, and type b mRNA is a major form among the three in most of the tissues examined [7].
  • Combined, these observations suggest that a cooperative function between Ogg1 and Mutyh exists to prevent 8-oxoG-related mutagenesis in mammals [8].
  • Type a and b mRNAs were expected to encode 57.7 kDa protein (MUTYHalpha), while type c mRNA had a partly different open reading frame encoding a 50.2 kDa protein (MUTYHbeta) [7].
  • The base excision repair carried out by bacterial MutY DNA glycosylase and eukaryotic MutY homolog (MYH) is responsible for removing adenines misincorporated into DNA opposite G and 7,8-dihydro-8-oxo-guanines (8-oxoG); thereby preventing G:C to T:A mutations [9].
 

Anatomical context of Mutyh

 

Associations of Mutyh with chemical compounds

  • In cell-free extract prepared from the thymocytes of wild type but not MUTYH-null mice, adenine opposite 8-oxoG in DNA was excised by MUTYH, however, the generated apurinic (AP) site opposite 8-oxoG mostly remained unincised [10].
  • MutY homolog (MUTYH) excises adenine opposite 8-oxoguanine (8-oxoG) in DNA, thus preventing occurrence of G:C to T:A transversion [10].
  • A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA [11].
  • Both mMYH variants exhibit a significantly decreased affinity for duplexes containing noncleavable 2'-deoxyadenosine analogues [12].
 

Other interactions of Mutyh

  • Functional cooperation of Ogg1 and Mutyh in preventing G: C-->T: a transversions in mice [8].

References

  1. Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-ras oncogene in lung tumors. Xie, Y., Yang, H., Cunanan, C., Okamoto, K., Shibata, D., Pan, J., Barnes, D.E., Lindahl, T., McIlhatton, M., Fishel, R., Miller, J.H. Cancer Res. (2004) [Pubmed]
  2. DNA damage recognition and repair by the murine MutY homologue. Pope, M.A., David, S.S. DNA Repair (Amst.) (2005) [Pubmed]
  3. MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intestinal tumorigenesis. Sakamoto, K., Tominaga, Y., Yamauchi, K., Nakatsu, Y., Sakumi, K., Yoshiyama, K., Egashira, A., Kura, S., Yao, T., Tsuneyoshi, M., Maki, H., Nakabeppu, Y., Tsuzuki, T. Cancer Res. (2007) [Pubmed]
  4. Accumulation of the oxidative base lesion 8-hydroxyguanine in DNA of tumor-prone mice defective in both the Myh and Ogg1 DNA glycosylases. Russo, M.T., De Luca, G., Degan, P., Parlanti, E., Dogliotti, E., Barnes, D.E., Lindahl, T., Yang, H., Miller, J.H., Bignami, M. Cancer Res. (2004) [Pubmed]
  5. Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/+) mice. Sieber, O.M., Howarth, K.M., Thirlwell, C., Rowan, A., Mandir, N., Goodlad, R.A., Gilkar, A., Spencer-Dene, B., Stamp, G., Johnson, V., Silver, A., Yang, H., Miller, J.H., Ilyas, M., Tomlinson, I.P. Cancer Res. (2004) [Pubmed]
  6. The physical map of Mus musculus chromosome 11 reveals evolutionary relationships with different syntenic groups of genes in Homo sapiens. Münke, M., Francke, U. J. Mol. Evol. (1987) [Pubmed]
  7. Identification and characterization of two forms of mouse MUTYH proteins encoded by alternatively spliced transcripts. Ichinoe, A., Behmanesh, M., Tominaga, Y., Ushijima, Y., Hirano, S., Sakai, Y., Tsuchimoto, D., Sakumi, K., Wake, N., Nakabeppu, Y. Nucleic Acids Res. (2004) [Pubmed]
  8. Functional cooperation of Ogg1 and Mutyh in preventing G: C-->T: a transversions in mice. Isogawa, A. Fukuoka Igaku Zasshi (2004) [Pubmed]
  9. MutY and MutY homologs (MYH) in genome maintenance. Lu, A.L., Bai, H., Shi, G., Chang, D.Y. Front. Biosci. (2006) [Pubmed]
  10. MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain. Tominaga, Y., Ushijima, Y., Tsuchimoto, D., Mishima, M., Shirakawa, M., Hirano, S., Sakumi, K., Nakabeppu, Y. Nucleic Acids Res. (2004) [Pubmed]
  11. A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA. Ushijima, Y., Tominaga, Y., Miura, T., Tsuchimoto, D., Sakumi, K., Nakabeppu, Y. Nucleic Acids Res. (2005) [Pubmed]
  12. Insight into the functional consequences of hMYH variants associated with colorectal cancer: distinct differences in the adenine glycosylase activity and the response to AP endonucleases of Y150C and G365D murine MYH. Pope, M.A., Chmiel, N.H., David, S.S. DNA Repair (Amst.) (2005) [Pubmed]
 
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