Human MutY Homolog, a DNA Glycosylase Involved in Base Excision Repair, Physically and Functionally Interacts with Mismatch Repair Proteins Human MutS Homolog 2/Human MutS Homolog 6

Gu, Yesong; Parker, Antony R.; Wilson, Teresa; Bai, Haibo; Chang, Dau-Yin; Lu, A-Lien

doi:10.1074/jbc.m108618200

Cited by 187 publications

(156 citation statements)

References 60 publications

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“…If mMUTYH(AA) protein without its PCNA interaction can excise adenine in the template DNA to which 8-oxo-G was inserted from nucleotide pool, A:T to C:G transversion mutation might be highly induced. Our results suggest that mMU-TYH(AA) or wild type mMUTYH can also interact with other components of post-replicative BER, as reported previously (19), thus ensuring the strand recognition. Alternatively, 8-oxodGTP produced in the nucleotide pool is efficiently sanitized by MTH1, thus preventing the incorporation of 8-oxo-G opposite adenine in the template DNA.…”

Section: Mutator Phenotype Of Mutyh-null Es Cells 38123supporting

confidence: 81%

Mutator Phenotype of MUTYH-null Mouse Embryonic Stem Cells

Hirano

Tominaga

Ichinoe

et al. 2003

Journal of Biological Chemistry

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To evaluate the antimutagenic role of a mammalian mutY homolog, namely the Mutyh gene, which encodes adenine DNA glycosylase excising adenine misincorporated opposite 8-oxoguanine in the template DNA, we generated MUTYH-null mouse embryonic stem (ES) cells. In the MUTYH-null cells carrying no adenine DNA glycosylase activity, the spontaneous mutation rate increased 2-fold in comparison with wild type cells. The expression of wild type mMUTYH or mutant mMUTYH protein with amino acid substitutions at the proliferating cell nuclear antigen binding motif restored the increased spontaneous mutation rates of the MUTYH-null ES cells to the wild type level. The expression of a mutant mMUTYH protein with an amino acid substitution (G365D) that corresponds to a germ-line mutation (G382D) found in patients with multiple colorectal adenomas could not suppress the elevated spontaneous mutation rate of the MUTYH-null ES cells. Although the recombinant mMUTYH(G365D) purified from Escherichia coli cells had a substantial level of adenine DNA glycosylase activity as did wild type MUTYH, no adenine DNA glycosylase activity was detected in the MUTYHnull ES cells expressing the mMUTYH(G365D) mutant protein. The germ-line mutation (G382D) of the human MUTYH gene is therefore likely to be responsible for the occurrence of a mutator phenotype in these patients.

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Section: Mutator Phenotype Of Mutyh-null Es Cells 38123supporting

confidence: 81%

Mutator Phenotype of MUTYH-null Mouse Embryonic Stem Cells

Hirano

Tominaga

Ichinoe

et al. 2003

Journal of Biological Chemistry

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“…Interactions between MSH6 and the BER protein, MUTYH, were first described by Gu et al 2 These authors could demonstrate that the MSH2/MSH6 heterodimer stimulates the DNA binding and glycosylase activities of MUTYH to misincorporated adenines opposite 8-OxoG. Interestingly, they found a physical interaction between MUTYH and MSH6 that was substantially decreased in MT1 cell lines with compound heterozygous MSH6 missense mutations (Asp1213Val and Val1260Ile) in the C-terminal region of MSH6.…”

Section: Discussionmentioning

confidence: 94%

“…The gene products of MSH6 and MSH2 form the MutSa heterodimeric protein complex, which recognises base -base mismatches and small insertiondeletion loops and initiates the repair by excising the mispaired base. 2 Thus, mutations in MSH6 decrease the capacity of the MMR system, resulting in augmentation of somatic mutations in tumour suppressor genes and oncogenes. 3 However, the penetrance of MSH6 mutations is lower compared to germline mutations of the MMR genes MLH1 and MSH2.…”

Section: Introductionmentioning

confidence: 99%

No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients

et al. 2008

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Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant tumour predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. In contrast to MLH1 and MSH2, germline mutations in MSH6 are associated with a milder and particularly variable phenotype. Based on the reported interaction of the MMR complex and the base excision repair protein MUTYH, it was hypothesised that MUTYH mutations serve as phenotypical modifiers in HNPCC families. Recently, a significantly higher frequency of heterozygosity for MUTYH mutations among MSH6 mutation carriers was reported. We examined 64 MSH6 mutation carriers (42 truncating mutations, 19 missense mutations and 3 silent mutations) of the German HNPCC Consortium for MUTYH mutations by sequencing the whole coding region of the gene. Monoallelic MUTYH mutations were identified in 2 of the 64 patients (3.1%), no biallelic MUTYH mutation carrier was found. The frequency of MUTYH mutations was not significantly higher than that in healthy controls, neither in the whole patient group (P ¼ 0.30) nor in different subgroups regarding mutation type. Our results do not support the association between MSH6 mutations and heterozygosity for MUTYH mutations.

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“…This suggests that hMYH interacting with ATR may be involved in the activation of ATR. hMYH physically and functionally interacts with several proteins for its role in replication and DNA repair, such as apurinic/apyrimidinic (AP) endonuclease (APE), RPA, and mutY homolog 6 (MSH6) (18,19). During checkpoint signaling http://bmbreports.org in response to DNA methylation in S phase, ATR-ATRIP is preferentially recruited to O6-MeG/T mismatches in a MutSα (a heterodimer of MSH2 and MSH6)-and hMutLα (a heterodimer of MLH1 and PMS2)-dependent manner.…”

Section: Discussionmentioning

confidence: 99%