Defective Base Excision Repair Associated with MUTYH

Stable Identifier
Homo sapiens
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MUTYH gene is located on chromosome 1 and encodes a DNA glycosylase involved in base excision repair (BER). MUTYH (MYH) functions as an adenine DNA glycosylase and removes adenines and 2-hydroxyadenines on the newly synthesized DNA strand mispaired with guanines or 8-oxoguanines. 8-oxogunanines are produced by oxidation of guanines in DNA or by incorporation of 8-oxodGTP from the nucleotide pool into the newly synthesized DNA strand. Germline mutations in MUTYH cause the MUTYH-associated polyposis (MAP), a syndrome that resembles the familial adenomatous polyposis (FAP) syndrome, caused by mutations in the APC tumor suppressor gene. MAP is also known as the familial adenomatous polyposis 2 (FAP2) (OMIM:608456). MAP-affected individuals are predisposed to development of multiple colorectal adenomas and colorectal cancer. MAP is largely inherited in an autosomally recessive manner, with both MUTYH alleles affected. The predisposition of heterozygous MUTYH mutation carriers to MAP has not been completely ruled out (Fleischmann et al. 2004).

MUTYH is most frequently affected by missense mutations in MAP patients, with two major mutations, Y165C and G382D, reported in about 80% of MAP patients of European origin. In Japanese patients, the most frequently reported mutation was Q324H (Yanaru-Fujisawa et al. 2008). Residues Y165C and G382D in the abundant MUTYH isoform MUTYH alpha-3 (MUTYH-3), used in the majority of functional studies, correspond to Y176C and G393D, respectively, in the canonical UniProt isoform (MUTYH alpha-1) and to Y179C and G396, respectively, in the longest NCBI isoform, which is used as a reference isoform in the database InSiGHT (International Society for Gastrointestinal Hereditary Tumours Database). However, both the canonical UniProt and NCBI MUTYH isoforms are expressed at very low levels or not at all (Plotz et al. 2012). In addition to the isoform MUTYH alpha-3, the other two abundant MUTYH isoforms are MUTYH beta-3 and MUTYH gamma-3 (Plotz et al. 2012), which differ from MUTYH alpha-3 in the first exon used. Exons 1-alpha and 1-beta contain sequences that resemble a mitochondrial targeting signal (MTS). It was reported that MUTYH alpha-3 and MUTYH beta-3 predominantly localize to mitochondria, while MUTYH gamma-3 predominantly localizes to the nucleus (Takao et al. 1999). However, a nuclear localization signal is located at the C-terminus of all MUTYH isoforms and other studies suggested that all isoforms can localize to the nucleus and only a small fraction of MUTYH is targeted to the mitochondria (Ohtsubo et al. 2000, Ichinoe et al. 2004). A small number of functional studies of MUTYH mutants uses the MUTYH isoform gama-3 (Goto et al. 2010, Shinmura et al. 2012). Nuclear localization of MUTYH may be affected by a splicing site variant (Tao et al. 2004).

MAP, compared with APC-associated FAP, is characterized by a later age of onset and a smaller number and size of polyps. Germline MUTYH mutations are associated with an increased incidence of duodenal polyps, gastric cancer, melanoma, breast cancer, dental and dermoid cysts, and osteomas. MUTYH mutations are rarely reported in the sporadic colorectal cancer. Tumors that develop in MAP patients are characterized with an excess of G:C -> T:A transversions in tumor suppressor genes, such as APC, and oncogenes, such as KRAS, which is a consequence of MUTYH functional impairment.

A single nucleotide polymorphism (SNP) at the splice donor site was reported to affect translation efficiency of MUTYH transcript, but its relevance for cancer predisposition has not been clarified (Yamaguchi et al. 2002). Catalytic activity of MUTYH and its mutants may be affected by posttranslational modifications (Parker et al. 2003, Kundu et al. 2010). Some MUTYH mutations reported in colorectal cancer do not affect MUTYH catalytic activity but disrupt the interaction of MUTYH with other proteins involved in DNA repair (Tominaga et al. 2004, Turco et al. 2013).

For review, please refer to Chow et al. 2004, Nielsen et al. 2011, Venesio et al. 2012, Mazzei et al. 2013.
Literature References
PubMed ID Title Journal Year
22473953 MUTYH gene expression and alternative splicing in controls and polyposis patients

Raedle, J, Casper, M, Zeuzem, S, Brieger, A, Trojan, J, Plotz, G, Hinrichsen, I, Heckel, V

Hum. Mutat. 2012
14991577 Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer

Shah, B, Fleischmann, C, Cheadle, J, Peto, J, Sampson, J, Houlston, RS

Int. J. Cancer 2004
15465463 Colorectal cancer and inherited mutations in base-excision repair

Lipton, L, Thirlwell, C, Chow, E, Macrae, F

Lancet Oncol. 2004
15199168 MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain

Mishima, M, Shirakawa, M, Nakabeppu, Y, Sakumi, K, Ushijima, Y, Tominaga, Y, Hirano, S, Tsuchimoto, D

Nucleic Acids Res. 2004
10471731 Differential subcellular localization of human MutY homolog (hMYH) and the functional activity of adenine:8-oxoguanine DNA glycosylase

Takao, M, Yasui, A, Zhang, QM, Yonei, S

Nucleic Acids Res. 1999
23460202 Understanding the role of the Q338H MUTYH variant in oxidative damage repair

Degan, P, Ventura, I, Mazzei, F, Molatore, S, Russo, MT, Ranzani, GN, Torreri, P, Turco, E, Minoprio, A, Bignami, M

Nucleic Acids Res. 2013
20848659 Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer

Shinmura, K, Goto, M, Sugimura, H, Tsuneyoshi, T, Nakabeppu, Y, Yamada, H, Tao, H

Hum. Mutat. 2010
12056405 A single nucleotide polymorphism at the splice donor site of the human MYH base excision repair genes results in reduced translation efficiency of its transcripts

Shinmura, K, Kuwano, H, Takenoshita, S, Saitoh, T, Yamaguchi, S, Yokota, J

Genes Cells 2002
23322991 Impaired suppressive activities of human MUTYH variant proteins against oxidative mutagenesis

Matsuura, S, Shinmura, K, Matsuda, T, Goto, M, Sugimura, H, Tao, H

World J. Gastroenterol. 2012
20663686 MUTYH-associated polyposis (MAP)

Vasen, HF, Hes, FJ, Nielsen, M, Morreau, H

Crit. Rev. Oncol. Hematol. 2011
12966098 Defective human MutY phosphorylation exists in colorectal cancer cell lines with wild-type MutY alleles

Sahin, F, Su, GH, Parker, AR, Eshleman, JR, Nelson, WG, DeWeese, TL, Racke, FK, O'Meally, RN

J. Biol. Chem. 2003
23507534 Role of MUTYH in human cancer

Viel, A, Mazzei, F, Bignami, M

Mutat. Res. 2013
15180946 A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus

Natsukawa, S, Kasuga, Y, Shaura, K, Ozawa, T, Shinmura, K, Tsugane, S, Sugimura, H, Li, Z, Koizumi, Y, Yamaguchi, S, Tsujinaka, T, Yokota, J, Hanaoka, T, Tao, H

Carcinogenesis 2004
22876359 MUTYH-associated polyposis (MAP), the syndrome implicating base excision repair in inherited predisposition to colorectal tumors

Ranzani, GN, D'Agostino, VG, Venesio, T, Balsamo, A

Front Oncol 2012
10684930 Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria

Nishioka, K, Fujiwara, T, Shimokawa, H, Oda, H, Iwai, S, Ohtsubo, T, Imaiso, Y, Nakabeppu, Y

Nucleic Acids Res. 2000
20724227 Ser 524 is a phosphorylation site in MUTYH and Ser 524 mutations alter 8-oxoguanine (OG): a mismatch recognition

Brinkmeyer, MK, Kundu, S, Eigenheer, RA, David, SS

DNA Repair (Amst.) 2010
Name Identifier Synonyms
familial adenomatous polyposis DOID:0050424 adenomatous polyposis of the colon
colorectal cancer DOID:9256
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Cross References
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