REV1 Is Implicated in the Development of Carcinogen-Induced Lung Cancer

Dumstorf, Chad A.; Mukhopadhyay, Suparna; Krishnan, Elangovan; Haribabu, Bodduluri; McGregor, W. Glenn

doi:10.1158/1541-7786.mcr-08-0399

Cited by 43 publications

(40 citation statements)

References 46 publications

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“…The majority of the mutations are inferred to have been caused by a lesion in the DNA, and the nature of the mutations, predominantly base-pair substitutions and small insertions and deletions, resemble those known to be introduced during mutagenic TLS (3,9). Rev1 also has been implicated in the development of carcinogeninduced lung cancer (32). Normal levels of TLS DNA polymerases, together with the large amounts of DNA damage from exogenous agents such as smoking or sunlight, might be sufficient to account for the many mutations observed in tumors.…”

Section: Discussionmentioning

confidence: 99%

Error-prone translesion synthesis mediates acquired chemoresistance

Xie¹,

Doles

Hemann

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

191

207

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The development of cancer drug resistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. Error-prone translesional DNA synthesis (TLS) is known to underlie the mutagenic effects of numerous anticancer agents, but little is known as to whether mutation induced by this process is ultimately relevant to tumor drug resistance. Here, we use a tractable mouse model of B-cell lymphoma to interrogate the role of error-prone translesional DNA synthesis in chemotherapyinduced mutation and resistance to front-line chemotherapy. We find that suppression of Rev1, an essential TLS scaffold protein and dCMP transferase, inhibits both cisplatin-and cyclophosphamideinduced mutagenesis. Additionally, by performing repeated cycles of tumor engraftment and treatment, we show that Rev1 plays a critical role in the development of acquired cyclophosphamide resistance. Thus, chemotherapy not only selects for drug-resistant tumor population but also directly promotes the TLS-mediated acquisition of resistance-causing mutations. These data provide an example of an alteration that prevents the acquisition of drug resistance in tumors in vivo. Because TLS also represents a critical mechanism of DNA synthesis in tumor cells following chemotherapy, these data suggest that TLS inhibition may have dual anticancer effects, sensitizing tumors to therapy as well as preventing the emergence of tumor chemoresistance.DNA polymerase | cancer | chemotherapy | relapse T he development of acquired chemoresistance is a persistent clinical problem limiting the successful treatment of disseminated malignancies. Tumors that relapse following initial treatment frequently are refractory to subsequent administration of the initial drug regimen as well as to distinct sets of chemotherapeutics. Although a number of key pathways have been implicated in resistance to conventional chemotherapeutics, including enhanced drug efflux, increased drug metabolism, drug inactivation, enhanced DNA repair, and defects in apoptosis programs (1, 2), the mechanisms by which tumors develop drug resistance-causing mutations remains unclear.At its core, acquired chemoresistance represents the emergence of subpopulations of drug-resistant tumor cells, a phenomenon rooted in the inherent genetic heterogeneity of the tumor itself. This heterogeneity may occur as a consequence of tumor genetic instability, a process known to underlie tumor development in numerous malignancies. Alternatively, cancer therapy itself may promote mutation and subsequent chemoresistance in relapsed tumors. Support for the latter hypothesis comes from several observations. First, conventional chemotherapeutics can be highly mutagenic (3). In fact, considerable work has gone into highlighting the mutagenic properties of platinum-based and other DNA adduct-forming chemotherapeutics as well as the genes that act in the cellular res...

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Section: Discussionmentioning

confidence: 99%

Error-prone translesion synthesis mediates acquired chemoresistance

Xie¹,

Doles

Hemann

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

191

207

View full text Add to dashboard Cite

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“…However, the Asn373Ser polymorphisms were not associated with an increased risk of lung cancer. Furthermore, the data from Dumstorf et al (21) supported that lowering the level of REV1 in mouse cells will after the mutagenic response after exposure to carcinogens such as benzo[a]pyrene. In Fanconi Anemia (FA), a syndrome characterized by congenital abnormalities, progression bone marrow failure, and elevated cancer susceptibility, REV1 is required to prevent DNA crosslinker-induced chromosome aberrations in human cells (22).…”

Section: Discussionmentioning

confidence: 99%

REV1 Genetic Polymorphisms and Breast Cancer Risk in Thai Women

Sangrajrang

Sato

Sanada

et al. 2011

Genes and Environment

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Genomic DNA is exposed to a constant insult from sources that are both endogenous and exogenous to the cell. REV1 protein, a eukaryotic member of Y family of DNA polymerases, is involved in the tolerance to such DNA damages by providing a translesion DNA synthesis. Here, we examined possible association between REV1 polymorphisms and breast cancer risk in Thai women. Five single nucleotide polymorphisms (SNPs) REV1 (rs3792152, rs3087395, rs3792137, rs959929, rs3087386) were genotyped. The study population consists of 570 patients with histopathologically conˆrmed breast cancer and 497 controls. Association of genotypes with breast cancer risk was evaluated using multivariate logistic regression to estimate odds ratios (OR) and their 95z conˆdence intervals (95zCI). Our results revealed that the heterozygote carrier of REV1 SNP (rs3087395) was associated with breast cancer risk with OR＝1.59 (95 zCI: 1.11-2.29). In addition, an increased risk was observed for homozygotes at the REV1 SNP (rs 959929) with the OR＝1.52 (95zCI: 1.01-2.29). A stratiˆed analysis suggested that the association between the REV1 SNPs and breast cancer is diŠerent by the menopausal status. The present results suggest that REV1 polymorphisms are likely to play a modifying role in the individual susceptibility to breast cancer among Thai women.

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“…While recent studies attributed acquired mutator phenotypes partly to the overexpression of APOBEC family proteins (49), little is known about how the remaining SNVs arise in tumor cells. Although, based on some data from our group and other investigators, Y-Pol-mediated mutagenesis is proposed to be involved in tumor progression through several mechanisms, such as elevated expression and Hsp90-mediated activation (11,26,27,(50)(51)(52)(53), how Y-Pols are activated during tumor progression is still poorly understood. In this regard, the present findings uncovered a previously unrecognized role of Y-Pols in cancer-associated aberrant replication, thus promoting our understanding of the functions of these polymerases during tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Both High-Fidelity Replicative and Low-Fidelity Y-Family Polymerases Are Involved in DNA Rereplication

Sekimoto

Oda

Kurashima

et al. 2015

Molecular and Cellular Biology

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b DNA rereplication is a major form of aberrant replication that causes genomic instabilities, such as gene amplification. However, little is known about which DNA polymerases are involved in the process. Here, we report that low-fidelity Y-family polymerases (Y-Pols), Pol , Pol , Pol , and REV1, significantly contribute to DNA synthesis during rereplication, while the replicative polymerases, Pol ␦ and Pol , play an important role in rereplication, as expected. When rereplication was induced by depletion of geminin, these polymerases were recruited to rereplication sites in human cell lines. This finding was supported by RNA interference (RNAi)-mediated knockdown of the polymerases, which suppressed rereplication induced by geminin depletion. Interestingly, epistatic analysis indicated that Y-Pols collaborate in a common pathway, independently of replicative polymerases. We also provide evidence for a catalytic role for Pol and the involvement of Pol and Pol in cyclin E-induced rereplication. Collectively, our findings indicate that, unlike normal S-phase replication, rereplication induced by geminin depletion and oncogene activation requires significant contributions of both Y-Pols and replicative polymerases. These findings offer important mechanistic insights into cancer genomic instability. E ukaryotic cells contain regulatory mechanisms to ensure that chromosomal DNA is duplicated exactly once per cell cycle (1-3). In late mitosis and early G 1 phase, replication origins are "licensed" through the formation of the prereplicative complex by sequential recruitment of the origin recognition complex, the loading factors Cdt1 and CDC6, and the minichromosome maintenance (MCM) 2-7 replicative helicase complex (MCM complex). At the onset of S phase, cyclin-dependent kinase 2 (CDK2)-and CDC7-mediated phosphorylation activates the MCM complex to unwind DNA, followed by loading of replication machinery to initiate DNA replication. Once cells enter S phase, the MCM complex is depleted from origins, and licensing of origins is inhibited during the S and G 2 phases by multiple mechanisms, including degradation of Cdt1 and CDC6 and expression of geminin, a specific inhibitor of Cdt1.Growing evidence indicates that DNA rereplication plays a major role in genomic instability during tumor development and progression (2-4). Importantly, expression of various oncoproteins in cultured cells induces rereplication, partly through the increased expression of Cdt1 and/or CDC6, causing copy number changes and genomic rearrangements (5-7). Furthermore, a recent study documented that overexpression of KDM4A demethylase causes rereplication, resulting in site-specific gene amplification in human tumors (8). Although the molecular mechanisms for rereplication-induced genomic instability are not fully understood, it is proposed that rereplication induces double-strand breaks (DSBs) through fork collapse and collisions, leading to copy number variations and genomic rearrangements (2-4). While numerous studies have focused on the causes ...

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REV1 Is Implicated in the Development of Carcinogen-Induced Lung Cancer

Cited by 43 publications

References 46 publications

Error-prone translesion synthesis mediates acquired chemoresistance

Error-prone translesion synthesis mediates acquired chemoresistance

REV1 Genetic Polymorphisms and Breast Cancer Risk in Thai Women

Both High-Fidelity Replicative and Low-Fidelity Y-Family Polymerases Are Involved in DNA Rereplication

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