DNA mismatch repair and its many roles in eukaryotic cells

Liu, Dekang; Keijzers, Guido; Rasmussen, Lene Juel

doi:10.1016/j.mrrev.2017.07.001

Cited by 147 publications

(116 citation statements)

References 266 publications

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“…MMR also suppresses homologous recombination and was recently reported to serve a role in DNA damage signaling. Defects in MMR are associated with genome-wide instability, predisposition to several types of human cancer, including ESCC, and resistance to certain chemotherapeutic agents (35,36). The cellular response to DNA damage is to limit viability, whilst initiating DNA repair.…”

Section: Discussionmentioning

confidence: 99%

shRNA‑mediated knockdown of KNTC1 suppresses cell viability and induces apoptosis in esophageal squamous cell carcinoma

et al. 2019

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Kinetochore-associated proteins are critical components of mitotic checkpoints, which are essential for faithful chromosomal segregation and spindle assembly during cell division. Recent advances have demonstrated that kinetochore-associated proteins are upregulated and serve significant roles in the carcinogenesis of numerous types of cancer. However, the effects of kinetochore-associated protein 1 (KNTC1) on human cancer, particularly on esophageal squamous cell carcinoma (ESCC), remain unclear. The present study revealed that KNTC1 was highly expressed in ESCC cell lines. Subsequently, lentivirus-mediated short hairpin RNAs were used to knockdown KNTC1 expression in human ESCC cell lines. Cell growth and viability were measured using multiparametric high-content screening and the MTT assay, respectively. Cell apoptosis was assessed by staining cells with Annexin V-allophycocyanin and was detected using FACScan flow cytometry. The results demonstrated that knockdown of KNTC1 effectively inhibited cell viability and increased apoptosis. In addition, a gene set enrichment analysis of online ESCC datasets indicated that KNTC1 overexpression was associated with increases in the mitotic spindle and hypoxia pathways, and decreases in the DNA repair and mismatch repair pathways. The findings of the present study suggested that KNTC1 may have an essential role in mediating cell viability and apoptosis in human ESCC cells and may serve as a novel therapeutic target for ESCC.

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Section: Discussionmentioning

confidence: 99%

shRNA‑mediated knockdown of KNTC1 suppresses cell viability and induces apoptosis in esophageal squamous cell carcinoma

et al. 2019

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“…15 The DNA mismatch repair (MMR) system, consisted of a set of specific enzymes and MMR proteins, play a key role in genome stability by correcting DNA replication errors in cells. 16 The major MMR proteins are MLH1, MSH2, and MSH6 and PMS2. 17 Mutations or down-regulation of expression occurring in these proteins coding genes could lead to MMR dysfunction, showing microsatellite instability (MSI); if the events of gene mutations continue to accumulates, eventually Lynch syndrome-associated tumours might be caused.…”

Section: Introductionmentioning

confidence: 99%

Methylation and expression analysis of mismatch repair genes in extramammary Paget's disease

Kang

Zhu

Zhang

et al. 2019

Acad Dermatol Venereol

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Background Extramammary Paget's disease (EMPD) is a rare skin cancer with relative high frequencies of germline and somatic mismatch repair (MMR) genes mutations. However, the methylation and expression of these genes have not been validated in EMPD. Objective This study aims to confirm the methylation and expression of MMR genes in EMPD.Methods Immunohistochemical (IHC) staining detection and Methylation-specific PCR (MSP) were used to analyse MLH1, MSH2, MSH6 and PMS2 proteins' expression and promoters' methylation in 57 EMMD samples, and pyrosequence was used to find highly methylated CpG sites in MSH2 promoter.Results Immunohistochemical detection displayed reduced expression of MSH2 in 38.6% EMPD cases but normal expression of MLH1, MSH6 and PMS2 in all tumour tissues. Hypermethylation also was found in the promoter of MSH2 but not in other MMR genes. Pyrosequencing of MSH2 promoter showed CpG6 (-87) and CpG3 (-98) were the most common two methylated CpG dinucleotides. There is a significant correlation between reduced MSH2 expression and MSH2 methylation.Conclusion Reduced MSH2 expression and hypermethylation in this gene promoter were common genetic changes in EMPD, which expands our understanding of the role of MMR function in this skin cancer.

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“…DSBs can be processed by a variety of homologous or nonhomologous pathways; for example, breaks with nonhomologous ends can be processed via nonhomologous end‐joining repair mechanisms, whereas homologous recombination repair (HR) is guided by sequence homology often provided by a sister chromatid during S‐phase repair. Mismatch repair (MMR) processes base‐base mismatches, and small loops or insertion/deletion mispairs generated during replication and recombination …”

Section: Dna Repairmentioning

confidence: 99%

“…Mismatch repair (MMR) processes base-base mismatches, and small loops or insertion/ deletion mispairs generated during replication and recombination. 235 Although the molecular mechanisms underlying the obesitycancer link are poorly understood, there is some mechanistic evidence to suggest that inefficient repair of DNA adducts formed as a result of obesity-induced metabolic changes may contribute to carcinogenesis.…”

Section: Dna Repairmentioning

confidence: 99%

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

Kompella

Vásquez

2019

Molecular Carcinogenesis

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Obesity, defined as a state of positive energy balance with a body mass index exceeding 30 kg/m2 in adults and 95th percentile in children, is an increasing global concern. Approximately one‐third of the world's population is overweight or obese, and in the United States alone, obesity affects one in six children. Meta‐analysis studies suggest that obesity increases the likelihood of developing several types of cancer, and with poorer outcomes, especially in children. The contribution of obesity to cancer risk requires a better understanding of the association between obesity‐induced metabolic changes and its impact on genomic instability, which is a major driving force of tumorigenesis. In this review, we discuss how molecular changes during adipose tissue dysregulation can result in oxidative stress and subsequent DNA damage. This represents one of the many critical steps connecting obesity and cancer since oxidative DNA lesions can result in cancer‐associated genetic instability. In addition, the by‐products of the oxidative degradation of lipids (e.g., malondialdehyde, 4‐hydroxynonenal, and acrolein), and gut microbiota‐mediated secondary bile acid metabolites (e.g., deoxycholic acid and lithocholic acid), can function as genotoxic agents and tumor promoters. We also discuss how obesity can impact DNA repair efficiency, potentially contributing to cancer initiation and progression. Finally, we outline obesity‐related epigenetic changes and identify the gaps in knowledge to be addressed for the development of better therapeutic strategies for the prevention and treatment of obesity‐related cancers.

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DNA mismatch repair and its many roles in eukaryotic cells

Cited by 147 publications

References 266 publications

shRNA‑mediated knockdown of KNTC1 suppresses cell viability and induces apoptosis in esophageal squamous cell carcinoma

shRNA‑mediated knockdown of KNTC1 suppresses cell viability and induces apoptosis in esophageal squamous cell carcinoma

Methylation and expression analysis of mismatch repair genes in extramammary Paget's disease

Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability

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