MSH2 and MSH6 Are Required for Removal of Adenine Misincorporated Opposite 8-Oxo-Guanine in S. cerevisiae

Ni, Terri T.; Marsischky, Gerald; Kolodner, Richard D.

doi:10.1016/s1097-2765(00)80346-9

Cited by 210 publications

(166 citation statements)

References 34 publications

(5 reference statements)

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“…In particular, MMR recognizes the mismatches in heteroduplex recombination intermediates, preventing completion of recombination between diverged sequences, thus promoting genetic stability (42)(43)(44). More recently, several groups have shown that MMR is involved in the repair of mismatched 8-oxoguanine, which is one of the major base lesions formed after DNA oxidative attack (45), and may participate in the transcriptioncoupled repair pathway (46,47). Cells with a defective MMR show a mutation rate 100-fold greater than that of normal cells, causing the accumulation of potentially deleterious mutations throughout the genome.…”

Section: Discussionmentioning

confidence: 99%

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Chang¹,

Jin

Yoon

et al. 2008

Molecular Cancer Research

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DNA damage and mutations in the genome increase with age. To determine the potential mechanisms of senescence-dependent increases in genomic instability, we analyzed DNA mismatch repair (MMR) efficiency in young and senescent human colonic fibroblast and human embryonic lung fibroblast. It was found that MMR activity is significantly reduced in senescent cells. Western blot and immunohistochemistry analysis revealed that hMSH2 and MSH6 protein (MutSA complex), which is a known key component in the MMR pathway, is markedly down-regulated in senescent cells. Moreover, the addition of purified MutSA to extracts from senescent cells led to the restoration of MMR activity. Semiquantitative reverse transcription-PCR analysis exhibited that MSH2 mRNA level is reduced in senescent cells. In addition, a decrease in E2F transcriptional activity in senescent cells was found to be crucial for MSH2 suppression. E2F1 small interfering RNA expression reduced hMSH2 expression and MMR activity in young human primary fibroblast cells. Importantly, expression of E2F1 in quiescent cells restored the MSH2 expression as well as MMR activity, whereas E2F1-infected senescent cells exhibited no restoration of MSH2 expression and MMR activity. These results indicate that the suppression of E2F1 transcriptional activity in senescent cells lead to stable repression of MSH2, followed by a induction of MutSA dysfunction, which results in a reduced cellular MMR capacity in senescent cells. (Mol Cancer Res 2008;6(6):978 -89)

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Section: Discussionmentioning

confidence: 99%

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Chang¹,

Jin

Yoon

et al. 2008

Molecular Cancer Research

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“…Finally, oxidative damage of DNA has been correlated with the ageing process. MutSα can target 8-oxo-guanine mispairs for repair (Mazurek et al, 2002;Ni et al, 1999), and treatment of HEL cells with H 2 O 2 is associated with a reduction in MMR and with decreased levels of some MMR proteins (see, e.g. Chang et al, 2002).…”

Section: Mmr and Ageingmentioning

confidence: 99%

DNA mismatch repair: Molecular mechanism, cancer, and ageing

Hsieh

Yamane

2008

Mechanisms of Ageing and Development

387

359

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DNA mismatch repair (MMR) proteins are ubiquitous players in a diverse array of important cellular functions. In its role in post-replication repair, MMR safeguards the genome correcting base mispairs arising as a result of replication errors. Loss of MMR results in greatly increased rates of spontaneous mutation in organisms ranging from bacteria to humans. Mutations in MMR genes cause hereditary nonpolyposis colorectal cancer, and loss of MMR is associated with a significant fraction of sporadic cancers. Given its prominence in mutation avoidance and its ability to target a range of DNA lesions, MMR has been under investigation in studies of ageing mechanisms. This review summarizes what is known about the molecular details of the MMR pathway and the role of MMR proteins in cancer susceptibility and ageing.

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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%

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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MSH2 and MSH6 Are Required for Removal of Adenine Misincorporated Opposite 8-Oxo-Guanine in S. cerevisiae

Cited by 210 publications

References 34 publications

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

DNA mismatch repair: Molecular mechanism, cancer, and ageing

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

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