Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol ζ

Brondello, Jean-Marc; Mj, Pillaire; Rodrı́guez, Carmen; Gourraud, Pierre-Antoine; Sèlves, Janick; Cazaux, Christophe; Piette, Jacques

doi:10.1038/onc.2008.212

Cited by 38 publications

(35 citation statements)

References 44 publications

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“…1 E and F). REV3L deficiency in human and mouse cell lines has been associated with double-strand breaks and chromosome instability (27,28). Consistent with these prior observations, we saw a relative increase in the number and intensity of γ-H2AX foci, a surrogate marker for DNA double-strand breaks, following cisplatin treatment of REV3L knockdown cells ( Fig.…”

Section: Resultssupporting

confidence: 79%

Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

Doles¹,

Oliver²,

Cameron³

et al. 2010

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

163

148

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Platinum-based chemotherapeutic drugs are front-line therapies for the treatment of non-small cell lung cancer. However, intrinsic drug resistance limits the clinical efficacy of these agents. Recent evidence suggests that loss of the translesion polymerase, Polζ, can sensitize tumor cell lines to cisplatin, although the relevance of these findings to the treatment of chemoresistant tumors in vivo has remained unclear. Here, we describe a tumor transplantation approach that enables the rapid introduction of defined genetic lesions into a preclinical model of lung adenocarcinoma. Using this approach, we examined the effect of impaired translesion DNA synthesis on cisplatin response in aggressive late-stage lung cancers. In the presence of reduced levels of Rev3, an essential component of Polζ, tumors exhibited pronounced sensitivity to cisplatin, leading to a significant extension in overall survival of treated recipient mice. Additionally, treated Rev3-deficient cells exhibited reduced cisplatin-induced mutation, a process that has been implicated in the induction of secondary malignancies following chemotherapy. Taken together, our data illustrate the potential of Rev3 inhibition as an adjuvant therapy for the treatment of chemoresistant malignancies, and highlight the utility of rapid transplantation methodologies for evaluating mechanisms of chemotherapeutic resistance in preclinical settings.

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Section: Resultssupporting

confidence: 79%

Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

Doles¹,

Oliver²,

Cameron³

et al. 2010

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

163

148

View full text Add to dashboard Cite

show abstract

“…On the one hand, REV3L was established to be necessary for proliferation of mouse embryonic fibroblasts, and inhibition of REV3L expression resulted in a pronounced growth arrest in Burkitt lymphoma, lung, breast, mesothelioma and colon cancer cells (6,18). In contrast, suppression of REV3L expression did not alter cell growth/survival in hct116, U2oS and heLa cancer cell lines (13,19). In the present study, we found that downregulation of REV3L expression decreased cell growth, migratory and invasive potential of ESCC cells.…”

Section: Discussionmentioning

confidence: 99%

REV3L, the catalytic subunit of DNA polymerase ζ, is involved in the progression and chemoresistance of esophageal squamous cell carcinoma

Zhu

Zou²,

Zhou

et al. 2016

Oncology Reports

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Abstract. Protein reversionless 3-like (REV3L), the catalytic subunit of DNA polymerase (pol) ζ, is well known to participate in error-prone translesion synthesis (TLS) with less stringent and lower processivity. Recent evidence has demonstrated that REV3L is involved in carcinogenesis and tumor progression. However, the function of REV3L remains unclear in esophageal squamous cell carcinoma (ESCC). In the present study, we examined REV3L expression in ESCC tissues and its association with clinicopathological parameters. REV3L was found to be significantly upregulated and correlated with lymph node metastasis and clinical stage in the ESCC tissues. To further investigate the potential role of REV3L in esophageal cancer, stable ESCC cell lines with suppression of REV3L expression were established. Downregulation of REV3L expression led to a decrease in cell proliferation and invasive capacity partly through suppression of cyclin D1 and survivin expression, and an increase in cellular sensitivity to 5-fluorouracil (5-FU) by induction of G1 phase arrest and apoptosis. Therefore, REV3L plays an important role in ESCC progression and chemoresistance, and is a potential diagnostic marker and therapeutic target for ESCC. IntroductionEsophageal squamous cell carcinoma (ESCC) is one of the most fatal malignancies with a relatively high incidence worldwide (1,2). Clinical evidence indicates that the etiology of ESCC includes multiple factors containing both environmental and genetic determinants (3). Although a high number of genetic and epigenetic alterations has been reported in ESCC, molecular markers for early diagnosis and prognosis remain to be discovered. The majority of ESCC deaths are due to invasive disease; therefore, identification of novel genes involved in the tumorigenesis and development of ESCC could contribute to improving the outcome of this disease.Translesion DNA synthesis (TLS) is one type of DNA damage tolerance mechanisms that allows continuing DNA synthesis even in the presence of DNA damage (4,5). Protein reversionless 3-like (Rev3L), the catalytic subunit of the DNA polymerase (pol) ζ, is well known to participate in errorprone TLS with less stringent and lower processivity (4). Rev3L maintains genomic integrity by inserting a substitute nucleotide in the opposite DNA adducts, which increases the mutation rate and contributes to carcinogenesis (6). Rev3L gene polymorphisms have been correlated with the risk of lung and breast cancer (7,8). Pol ζ was reported to promote tumor formation and is significantly associated with poor progression in cervical cancer (9,10). Thus, Rev3L may play an important role in carcinogenesis and tumor progression.The REV3L gene appears to be ubiquitously expressed in normal and tumor tissues, while its expression pattern remains contentious in different cancer tissues (11,12). REV3L expression was found to be downregulated in colon, lung, gastric and renal cancer tissues as compared to adjacent tissues (13), whereas it was found to be upregulated in human glioma tiss...

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“…Rev7 overexpression has been found in colon cancer, and this correlates with chromosomal instability and patient mortality (222). Curiously, another study found that rev3 transcript levels were downregulated in colon carcinomas (25). The contradictory data reveal the complexity of cancer and suggest that TLS polymerases could have roles in cancer in specific contexts.…”

Section: Pol (Rev3/rev7)mentioning

confidence: 99%

“…REV3 transcript levels are upregulated above the normally low basal levels in late meiosis in yeast (234). Reminiscent of the cell cycle regulation of Rev1 in S. cerevisiae, Rev3 chromatin association in human cells has a cell cycle-regulated pattern, showing highest levels during the G 1 /S boundary, which decreased during S phase and increased again during late S and G 2 (25).…”

Section: Pol (Rev3/rev7)mentioning

confidence: 99%

Eukaryotic Translesion Polymerases and Their Roles and Regulation in DNA Damage Tolerance

Waters

Minesinger

Wiltrout

et al. 2009

Microbiol Mol Biol Rev

524

647

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SUMMARY DNA repair and DNA damage tolerance machineries are crucial to overcome the vast array of DNA damage that a cell encounters during its lifetime. In this review, we summarize the current state of knowledge about the eukaryotic DNA damage tolerance pathway translesion synthesis (TLS), a process in which specialized DNA polymerases replicate across from DNA lesions. TLS aids in resistance to DNA damage, presumably by restarting stalled replication forks or filling in gaps that remain in the genome due to the presence of DNA lesions. One consequence of this process is the potential risk of introducing mutations. Given the role of these translesion polymerases in mutagenesis, we discuss the significant regulatory mechanisms that control the five known eukaryotic translesion polymerases: Rev1, Pol ζ, Pol κ, Pol η, and Pol ι.

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Novel evidences for a tumor suppressor role of Rev3, the catalytic subunit of Pol ζ

Cited by 38 publications

References 44 publications

Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

Suppression of Rev3, the catalytic subunit of Polζ, sensitizes drug-resistant lung tumors to chemotherapy

REV3L, the catalytic subunit of DNA polymerase ζ, is involved in the progression and chemoresistance of esophageal squamous cell carcinoma

Eukaryotic Translesion Polymerases and Their Roles and Regulation in DNA Damage Tolerance

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