Mismatch Repair Pathway, Genome Stability and Cancer

Pećina‐Šlaus, Nives; Kafka, Anja; Salamon, Iva; Bukovac, Anja

doi:10.3389/fmolb.2020.00122

Cited by 177 publications

(163 citation statements)

References 102 publications

(146 reference statements)

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“…DNA double-strand breaks (DSBs) are genomic lesions that may lead to carcinogenesis if left unrepaired or not properly repaired. The major pathways participating in DNA damage detection and repair are: (i) the nucleotide excision repair (NER) pathway, involved in eliminating bulky adducts; (ii) the mismatch repair (MMR) involved in recognition of errors occurring during DNA replication and homologous recombination (HR) or non-homologous end joining (NHEJ), eventually recognizing and repairing DSBs; (iii) the base excision repair (BER) pathways, involved in oxidative damage to DNA bases and single-strand breaks (SSBs) [ 10 , 11 , 12 , 13 , 14 ].…”

Section: Dna Repair and Cellular Transformationmentioning

confidence: 99%

Tampering of Viruses and Bacteria with Host DNA Repair: Implications for Cellular Transformation

Benedetti

Curreli

Gallo

et al. 2021

Cancers

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A reduced ability to properly repair DNA is linked to a variety of human diseases, which in almost all cases is associated with an increased probability of the development of cellular transformation and cancer. DNA damage, that ultimately can lead to mutations and genomic instability, is due to many factors, such as oxidative stress, metabolic disorders, viral and microbial pathogens, excess cellular proliferation and chemical factors. In this review, we examine the evidence connecting DNA damage and the mechanisms that viruses and bacteria have evolved to hamper the pathways dedicated to maintaining the integrity of genetic information, thus affecting the ability of their hosts to repair the damage(s). Uncovering new links between these important aspects of cancer biology might lead to the development of new targeted therapies in DNA-repair deficient cancers and improving the efficacy of existing therapies. Here we provide a comprehensive summary detailing the major mechanisms that viruses and bacteria associated with cancer employ to interfere with mechanisms of DNA repair. Comparing these mechanisms could ultimately help provide a common framework to better understand how certain microorganisms are involved in cellular transformation.

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Section: Dna Repair and Cellular Transformationmentioning

confidence: 99%

Tampering of Viruses and Bacteria with Host DNA Repair: Implications for Cellular Transformation

Benedetti

Curreli

Gallo

et al. 2021

Cancers

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“… 4 The MMR system is composed of a set of proteins that interact as heterodimers to sense and repair unpaired bases and small loops formed by insertions or deletions. 5 These components are encoded by 8 genes, including hMSH2, hMSH3, hMSH5, hMSH6, hMLH1, hPMS1 (hMLH2), hMLH3, hPMS2 (hMLH4). 6 – 8 In the absence of a functional MMR system, the insertion-deletion mutation was not repaired, resulting in a new allele with a length change.…”

Section: Introductionmentioning

confidence: 99%

<p>Implication of Microsatellite Instability in Chinese Cohort of Human Cancers</p>

Cui¹,

Pan²,

Mao³

et al. 2020

CMAR

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Background: Microsatellite instability (MSI) has been a hot topic in cancer research. Determining MSI status greatly aids tumor prognosis and treatment plans. However, MSI data for Asian cancer patients with prognostic information are scarce. Here, our aim was to clarify MSI status and its prognostic value in a large Chinese cohort with different tumors. Patients and Methods: Tissue samples from 600 Chinese cases, including 150 endometrial cancers, 150 colorectal cancers, 150 liver cancers and 150 gastric cancers, were used for IHC and MSI examinations. Two mononucleotide and three dinucleotide markers were used to analyze MSI status. Results: In total,17.3% (26/150) of endometrial cancer patients showed positive MSI,10.0% (15/150) in colorectal cancer, 2.7% (4/150) in liver cancer, and 2.7% (4/150) in gastric cancer. Tumor location (P < 0.001 for colorectal cancer) and clinical stage (P =0.038 for gastric cancer) showed significant correlations with MSI status in gastrointestinal carcinogenesis. The mismatch repair (MMR) deficiency was observed in 20 colorectal cases (13.3%) and was significantly more frequent in the MSI-positive group (P < 0.001). Interestingly, the prevalence of MSI-H was mostly occurred in early-stage tumors, and none was in late stage (stage IV). Meanwhile, low clinicopathological stage had significant correlation with longer survival in multiple cancers here. Conclusion: The incidence of microsatellite instability varies among different cancer types. And the prevalence of MSI-H mostly occurred early clinicopathological stage. In addition, our study provided a large Asian cohort screened by five loci PCR method and significantly increased knowledge on the prognostic significance of MSI in Asia.

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“…MMR plays a crucial role in regulating tumor gene mutation 37 . The abnormal expression of MMR-related proteins is also related to tumor drug resistance 38 . In the case of leukemia, Diouf et al observed that the protein level of DNA mismatch repair protein MSH2 in 11% of childhood acute lymphoblastic leukemia cells decreased significantly and was resistant to mercaptopurine 39 .…”

Section: Discussionmentioning

confidence: 99%

Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia by inhibiting MSH2

Liu

Wang

et al. 2021

Cell Death Dis

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Nuclear factor erythroid 2-related factor 2 (Nrf2, also called NFE2L2) plays an important role in cancer chemoresistance. However, little is known about the role of Nrf2 in tumor mutation burden and the effect of Nrf2 in modulating DNA mismatch repair (MMR) gene in acute myeloid leukemia (AML). Here we show that Nrf2 expression is associated with tumor mutation burden in AML. Patients with Nrf2 overexpression had a higher frequency of gene mutation and drug resistance. Nrf2 overexpression protected the AML cells from apoptosis induced by cytarabine in vitro and increased the risk of drug resistance associated with a gene mutation in vivo. Furthermore, Nrf2 overexpression inhibited MutS Homolog 2 (MSH2) protein expression, which caused DNA MMR deficiency. Mechanistically, the inhibition of MSH2 by Nrf2 was in a ROS-independent manner. Further studies showed that an increased activation of JNK/c-Jun signaling in Nrf2 overexpression cells inhibited the expression of the MSH2 protein. Our findings provide evidence that high Nrf2 expression can induce gene instability-dependent drug resistance in AML. This study demonstrates the reason why the high Nrf2 expression leads to the increase of gene mutation frequency in AML, and provides a new strategy for clinical practice.

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Mismatch Repair Pathway, Genome Stability and Cancer

Cited by 177 publications

References 102 publications

Tampering of Viruses and Bacteria with Host DNA Repair: Implications for Cellular Transformation

Tampering of Viruses and Bacteria with Host DNA Repair: Implications for Cellular Transformation

<p>Implication of Microsatellite Instability in Chinese Cohort of Human Cancers</p>

Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia by inhibiting MSH2

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