Defective MUTYH mutants do not cleave adenine mispaired with 8-oxoguanine

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Homo sapiens
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MUTYH alpha-3 isoform (MUTYH-3) mutants MUTYH-3 Y165C and MUTYH-3 G382D have impaired ability to cleave adenine mispaired with 8-oxoguanine (OGUA:Ade, also known as 8-oxoG:A), and also show a reduced binding to the OGUA:Ade substrate (Jones et al. 2002, Chmiel et al. 2003, Wooden et al. 2004, Parker et al. 2005, Ali et al. 2008, Molatore et al. 2010, D'Agostino et al. 2010, Raetz et al. 2012). Impairment of catalytic activity was confirmed for the corresponding MUTYH gamma-3 isoform (MUTYH-6) mutants, MUTYH-6 Y151C and MUTYH-6 G368D (Gotto et al. 2010). Residues Y165 and G382 are conserved in mutY of Escherichia coli (Y82 and G253). Introduction of Y82C and G253D mutations into E. coli mutY significantly reduces the catalytic activity of bacterial mutY towards the OGUA:Ade substrate (Al-Tassan et al. 2002, Chmiel et al. 2003). MUTYH-3 Y165C and MUTYH-3 G382D are the two most common MUTYH mutations in patients of European origin affected by MUTYH-associated polyposis (MAP), also known as familial adenomatous polyposis 2 (FAP2) (Sieber et al. 2003, Sampson et al. 2003).

MUTYH-3 Q324H was reported as the most prevalent mutant in Japanese MAP patients (Yanaru-Fujisawa et al. 2008), and results in partial impairment of MUTYH DNA glycosylase activity (Ali et al. 2008). Q324H is a common polymorphism in some populations (Sampson et al. 2003, Raetz et al. 2012) but is associated with reduced catalytic activity of MUTYH and predisposition to cancer (Raetz et al. 2012).

MUTYH mutant MUTYH-3 R227W is unable to bind and process the OGUA:Ade substrate, while the MUTYH-3 V232F mutant shows severely reduced binding and catalytic activity towards OGUA:Ade. Neither MUTYH-3 R227W nor MUTYH-3 V232F can complement the mutY deficient E. coli cells (Bai et al. 2005). Mutation R231L lies in the same region and MUTYH-3 R231L mutants also show impaired binding to OGUA:Ade and no glycosylase activity. As expected, MUTYH-3 R231L was unable to complement E. coli mutY mutants (Bai et al. 2007). MUTYH-3 R231H mutant, defective in DNA binding and glycosylase activity, was reported in both adenomatous polyposis (Ali et al. 2008) and lung squamous cell carcinoma.

MUTYH-3 A459D mutant shows significantly reduced repair of OGUA:Ade mismatch and cannot complement the defective mutY in E. coli (Alhopuro et al. 2005).

Mutants MUTYH-3 G272E and MUTYH-3 A359V, reported in Japanese patients with adenomatous polyposis and wild-type APC gene, have impaired DNA glycosylase activity, based on studies with mouse Mutyh proteins carrying synonymous mutations. Affected residues, G272 and A359, are conserved in prokaryotic mutY and mouse Mutyh (Yanaru-Fujisawa et al. 2008). MUTYH-3 A359S mutant was reported in medulloblastoma (Pugh et al. 2012). This mutant has not been functionally tested, but is predicted to be pathogenic and is annotated as a candidate LOF mutant.

Mutants MUTYH-3 R260Q and MUTYH-3 P281L show impaired DNA binding and glycosylase activity, with MUTYH-3 P281L being more severely affected (Ali et al. 2008). In addition to adenomatous polyposis, MUTYH-3 R260Q was reported in stomach cancer and primary sclerosing cholangitis, a risk factor for development of cholangiocarcinoma (Forsbring et al. 2009). MUTYH-3 R260W mutant was detected in melanoma, skin squamous cell carcinoma, and chondrosarcoma (Tarpey et al. 2013, Pickering et al. 2014, Li et al. 2015). R260W substitution is predicted to be pathogenic, but has not been functionally tested, and therefore MUTYH-3 R260W was annotated as a candidate LOF mutant.

Mutants MUTYH-3 P391L and MUTYH-3 Q324R show reduced DNA glycosylase activity. While MUTYH-3 Q324R is able to complement E. coli mutY mutants, MUTYH-3 P391L is not (Kundu et al. 2009). MUTYH-6 P377L, a gamma-3 isoform mutant corresponding to MUTYH-3 P391L, is also not functional (Goto et al. 2010, Shinmura et al. 2012).

Loss-of-function of MAP-associated MUTYH mutants MUTYH-3 R171W, MUTYH-3 W138_M139insIW (also known as MUTYH 137insIW) and MUTYH-3 E466del was confirmed by expression of recombinant human proteins in Mutyh knockout mouse cells and measuring accumulation of OGUA in the genome and hypersensitivity to oxidative stress (Molatore et al. 2010), as well as by in vitro evaluation of their catalytic activity using the surface plasmon resonance technology (D'Agostino et al. 2010). Loss-of-function was also confirmed for MUTYH-6 E452del mutant, which corresponds to MUTYH-3 E466del (Goto et al. 2010).

Frameshift mutations in MUTYH, which result in MUTYH protein truncation, also occur in MAP patients. The frameshift mutants MUTYH-3 Y90fs*, MUTYH-3 Q377fs*, MUTYH-3 E466fs* and MUTYH-3 A368fs26* (commonly known as MUTYH 1103delC) are neither able to bind target DNA nor excise adenine mispaired with OGUA (Ali et al. 2008).

Impaired catalytic activity was shown for MUTYH gamma-3 isoform mutants MUTYH-6 I195V, MUTYH-6 M255V, MUTYH-6 R154H and MUTYH-3 L360P, but the corresponding alpha-3 isoform mutants have not been tested (Goto et al. 2010, Shinmura et al. 2012). A MUTYH missense mutation corresponding to R154H was reported in pancreatic ductal adenocarcinoma (Witkiewicz et al. 2015).

Literature References
PubMed ID Title Journal Year
15987719 Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair

Parker, AR, Sieber, OM, Shi, C, Hua, L, Takao, M, Tomlinson, IP, Eshleman, JR

Carcinogenesis 2005
20418187 Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis

D'Agostino, VG, Minoprio, A, Torreri, P, Marinoni, I, Bossa, C, Petrucci, TC, Albertini, AM, Ranzani, GN, Bignami, M, Mazzei, F

DNA Repair (Amst.) 2010
18534194 Characterization of mutant MUTYH proteins associated with familial colorectal cancer

Ali, M, Kim, H, Cleary, S, Cupples, C, Gallinger, S, Bristow, R

Gastroenterology 2008
12628248 Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer: complementation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E.coli enzymes

Chmiel, NH, Livingston, AL, David, SS

J. Mol. Biol. 2003
19953527 MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay

Molatore, S, Russo, MT, D'Agostino, VG, Barone, F, Matsumoto, Y, Albertini, AM, Minoprio, A, Degan, P, Mazzei, F, Bignami, M, Ranzani, GN

Hum. Mutat. 2010
16134146 A novel functionally deficient MYH variant in individuals with colorectal adenomatous polyposis

Alhopuro, P, Parker, AR, Lehtonen, R, Enholm, S, Järvinen, HJ, Mecklin, JP, Karhu, A, Eshleman, JR, Aaltonen, LA

Hum. Mutat. 2005
12606733 Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH

Sieber, OM, Lipton, L, Crabtree, M, Heinimann, K, Fidalgo, P, Phillips, RK, Bisgaard, ML, Orntoft, TF, Aaltonen, LA, Hodgson, SV, Thomas, HJ, Tomlinson, IP

N. Engl. J. Med. 2003
19443904 Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma

Forsbring, M, Vik, ES, Dalhus, B, Karlsen, TH, Bergquist, A, Schrumpf, E, Bjørås, M, Boberg, KM, Alseth, I

Carcinogenesis 2009
15673720 Functional characterization of two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis

Bai, H, Jones, S, Guan, X, Wilson, TM, Sampson, JR, Cheadle, JP, Lu, AL

Nucleic Acids Res. 2005
12393807 Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations

Jones, S, Emmerson, P, Maynard, J, Best, JM, Jordan, S, Williams, GT, Sampson, JR, Cheadle, JP

Hum. Mol. Genet. 2002
20848659 Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer

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

Hum. Mutat. 2010
23322991 Impaired suppressive activities of human MUTYH variant proteins against oxidative mutagenesis

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

World J. Gastroenterol. 2012
22926731 Cancer-associated variants and a common polymorphism of MUTYH exhibit reduced repair of oxidative DNA damage using a GFP-based assay in mammalian cells

Raetz, AG, Xie, Y, Kundu, S, Brinkmeyer, MK, Chang, C, David, SS

Carcinogenesis 2012
17081686 Functional characterization of human MutY homolog (hMYH) missense mutation (R231L) that is linked with hMYH-associated polyposis

Bai, H, Grist, S, Gardner, J, Suthers, G, Wilson, TM, Lu, AL

Cancer Lett. 2007
19836313 Adenine removal activity and bacterial complementation with the human MutY homologue (MUTYH) and Y165C, G382D, P391L and Q324R variants associated with colorectal cancer

Kundu, S, Brinkmeyer, MK, Livingston, AL, David, SS

DNA Repair (Amst.) 2009
15036665 Identification of critical residues required for the mutation avoidance function of human MutY (hMYH) and implications in colorectal cancer

Wooden, SH, Bassett, HM, Wood, TG, McCullough, AK

Cancer Lett. 2004
Participant Of
Normal reaction
Inferred From
Name Identifier Synonyms
colorectal cancer 9256
familial adenomatous polyposis 0050424 adenomatous polyposis of the colon
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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