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, Yi; Yang, Hanjing; Cunanan, Cristina; Okamoto, Kimberly; Shibata, Darryl; Pan, Janet L.; Barnes, Deborah E.; Lindahl, Tomas; McIlhatton, Michael A.; Fishel, Richard; Miller, Jeffrey H

doi:10.1158/0008-5472.can-03-3834

Cited by 271 publications

(216 citation statements)

References 32 publications

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“…It is possible that MYH mutations may have a largely permissive role in tumorigenesis through polyp formation, with subsequent progression occurring as a result of changes to other key genes. This role of MYH mutations in colorectal carcinogenesis is consistent with the finding in murine models that MYH knockouts are phenotypically normal (Xie et al, 2004).…”

Section: Discussionsupporting

confidence: 89%

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

et al. 2006

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Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

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Section: Discussionsupporting

confidence: 89%

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

et al. 2006

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“…In addition to correcting single base replication errors involving undamaged bases, several studies have shown that Msh6 (but not Msh3) also participates in correcting mismatches resulting from replication of 8-oxo-G, a common lesion generated by oxidative stress [33][34][35][36][37][38]. A signature of oxidative stress-induced substitutions is a G-C to T-A transversion, which results when dAMP is incorporated opposite 8-oxo-G in its syn conformation in the template strand [39].…”

Section: The Function Of Glu339 In Yeast Msh6mentioning

confidence: 99%

“…This explanation, among others, for the highly specific MMR defect conferred by the E339A mutation would undoubtedly benefit from structural information on Msh2-Msh6 bound to different mismatches and from functional studies involving initial binding and post-binding events. Studies of the phenotypes of mice containing the equivalent of the yeast Msh6 E339A mutation could also be informative regarding the contribution of substitution mutations caused by oxidative stress to disease (e.g., see [38]). The percentage of replication errors that are unrepaired by the mutant MutS or Msh6 enzymes was calculated as follows: ((MR mutant -MR wild type)/(MR null -MR wild type))*100, where MR stands for MR of the specific mutations, i.e.…”

Section: The Function Of Glu339 In Yeast Msh6mentioning

confidence: 99%

Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6

et al. 2007

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The major eukaryotic mismatch repair (MMR) pathway requires Msh2-Msh6, which, like E. coli MutS, binds to and participates in repair of the two most common replication errors, single base-base and single base insertion-deletion mismatches. For both types of mismatches, the side chain of E. coli Glu38 in a conserved Phe-X-Glu motif interacts with a mismatched base. The Oε of Glu38 forms a hydrogen bond with either the N7 of purines or the N3 of pyrimidines. We show here that changing E. coli Glu38 to alanine results in nearly complete loss of repair of both single base-base and single base deletion mismatches. In contrast, a yeast strain with alanine replacing homologous Glu339 in Msh6 has nearly normal repair for insertion-deletion and most base-base mismatches, but is defective in repairing base-base mismatches characteristic of oxidative stress, e.g., 8-oxo-G•A mismatches. The results suggest that bacterial MutS and yeast Msh2-Msh6 differ in how they recognize and/or process replication errors involving undamaged bases, and that Glu339 in Msh6 may have a specialized role in repairing mismatches containing oxidized bases.

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“…We point out that complete deletion of the OGG1 gene in mice does not result in tumorigenesis unless the MYH DNA glycosylase is also deleted. 58 Thus, as long as the adenine is removed from 8-oxoG:A mispairs by MYH, high levels of mutagenesis are unlikely to occur. In cells lacking OGG1, the MYH DNA glycosylase is also most likely acting in a functionally redundant manner to the missing enzyme, keeping levels of this adduct relatively low.…”

mentioning

confidence: 99%

“…In cells lacking OGG1, the MYH DNA glycosylase is also most likely acting in a functionally redundant manner to the missing enzyme, keeping levels of this adduct relatively low. 58,59 However, because humans live much longer than mice, slightly elevated levels of 8-oxo-G over a long period of time could be linked to mutations and cancer etiology. In addition, the tumor microenvironment is much different than that of normal cells.…”

mentioning

confidence: 99%

Is Base Excision Repair a Tumor Suppressor Mechanism?

Sweasy¹,

Lang²,

DiMaio³

2006

Cell Cycle

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The base excision repair pathway is critical for the removal of oxidized and methylated bases from the DNA. Much of this DNA damage arises endogenously, as a result of oxygen metabolism. Several proteins including DNA glycosylases, the APE1 endonuclease, DNA polymerase β and DNA ligase, act in a highly regulated and coordinated manner during base excision repair to excise the base adducts from the DNA and restore the normal DNA sequence. Both germline and tumor-associated variants of genes encoding these proteins have been identified in humans. In many cases, the protein variant has been shown to have properties that could contribute to the development of cancer, suggesting that base excision repair acts as a tumor suppressor mechanism in humans. Limited epidemiological studies are consistent with this view. Our review of the literature indicates that additional laboratory and epidemiological studies of the role of base excision repair in cancer etiology is warranted.

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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

Cited by 271 publications

References 32 publications

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer

Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6

Is Base Excision Repair a Tumor Suppressor Mechanism?

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