Transcription-Coupled Repair Deficiency and Mutations in Human Mismatch Repair Genes

Mellon, Isabel; Rajpal, Deepak K.; Koi, Minoru; Boland, C. Richard; Champe, Gregory N.

doi:10.1126/science.272.5261.557

Cited by 261 publications

(116 citation statements)

References 40 publications

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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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“…MSI in lung cancer occurs at a low frequency (Benachenhou et al, 1998). However, MMR proteins are involved in a variety of other cellular processes such as homologous recombination (de Wind et al, 1995), mediation of the G2 checkpoint (Meyers et al, 1997;Davis et al, 1998), the signalling pathway and transcriptioncoupled nucleotide excision repair (Mellon et al, 1996). Genedosage effects and reduced expression of MMR proteins have been suggested as risk factors (Wei et al, 1996(Wei et al, , 1998Benachenhou et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

et al. 2001

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Summary Carcinogenesis results from an accumulation of several genetic alterations. Mutations in the p53 gene are frequent and occur at an early stage of lung carcinogenesis. Loss of multiple chromosomal regions is another genetic alteration frequently found in lung tumours. We have examined the association between p53 mutations, loss of heterozygosity (LOH) at frequently deleted loci in lung cancer, and tobacco exposure in 165 tumours from non-small cell lung cancer (NSCLC) patients. A highly significant association between p53 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was also a significant correlation between deletions at these loci. 86% of the tumours with concordant deletion in the 4 most involved loci (3p21, 5q11-13, 9p21 and 17p13) had p53 mutations as compared to only 8% of the tumours without deletions at the corresponding loci (P < 0.0001). Data were also examined in relation to smoking status of the patients and histology of the tumours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hMLH1 locus), 3p14.2 (FHIT locus), 5q11-13 (hMSH3 locus) and 9p21 (D9S157 locus). Tumours with deletions at the hMLH1 locus had higher levels of hydrophobic DNA adducts. Deletions were more common in squamous cell carcinomas than in adenocarcinomas. Covariate analysis revealed that histological type and p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobacco carcinogens in addition to clonal selection may be the driving force in these alterations.

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“…Therefore, a gene dosage effect affecting the stoichiometry and the activity of the heteromolecular mismatch-repair complex may be sufficient to promote cancer by impairing functions other than the correction of replication errors. Mismatchrepair proteins are involved in a variety of vital cellular processes, including the homologous recombination (Jones et al, 1987;deWind et al, 1995), the mediation of the G2 checkpoint (Hawn et al, 1995), transcription-coupled nucleotide excision repair (Mellon et al, 1996) and in the recognition of DNA damage and/or in the signalling pathway contributing to the generation of apoptotic cells (Kat et al, 1993;Mu et al, 1997). Interestingly, the influence of environmental factors on the genome stability in cells defective in nucleotide excision repair and mismatch-repair could be substantial.…”

Section: Discussionmentioning

confidence: 99%

Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer

et al. 1999

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SummaryTo study the involvement of DNA mismatch-repair genes in sporadic breast cancer, matched normal and tumoral DNA samples of 22 patients were analysed for genetic instability and loss of heterozygosity (LOH) with 42 microsatellites at or linked to hMLH1 (3p21), hMSH2 (2p16), hMSH3 (5q11-q13), hMSH6 (2p16), hPMS1 (2q32) and hPMS2 (7p22) loci. Chromosomal regions 3p21 and 5q11-q13 were found hemizygously deleted in 46% and 23% of patients respectively. Half of the patients deleted at hMLH1 were also deleted at hMSH3. The shortest regions of overlapping (SRO) deletions were delimited by markers D3S1298 and D3S1266 at 3p21 and by D5S647 and D5S418 at 5q11-q13. Currently, the genes hMLH1 (3p21) and hMSH3 (5q11-q13) are the only known candidates located within these regions. The consequence of these allelic losses is still unclear because none of the breast cancers examined displayed microsatellite instability, a hallmark of mismatch-repair defect during replication error correction. We suggest that hMLH1 and hMSH3 could be involved in breast tumorigenesis through cellular functions other than replication error correction.

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Transcription-Coupled Repair Deficiency and Mutations in Human Mismatch Repair Genes

Cited by 261 publications

References 40 publications

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Senescence-Dependent MutSα Dysfunction Attenuates Mismatch Repair

Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer

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