A Role for Polymerase η in the Cellular Tolerance to Cisplatin-Induced Damage

Albertella, Mark R.; Green, Catherine; Lehmann, Alan R.; O’Connor, Mark J.

doi:10.1158/0008-5472.can-05-1095

Cited by 196 publications

(200 citation statements)

References 35 publications

(49 reference statements)

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“…Although results from yeast suggest that pol η does not confer resistance to ICL by cisplatin [5], XP-V cells have been reported to be hypersensitive to and impaired in the repair of a number of DNA damaging agents, including ICL-forming agents, suggesting that TLS by pol η is important in lesion tolerance and survival following ICL in humans [17,20,32,39]. However, most prior studies of pol η and ICLs have been performed utilizing plasmid substrates, rather than analyzing genomic DNA [18][19][20].…”

Section: Discussionmentioning

confidence: 99%

“…XP30RO and XP-var1 are SV40-transformed fibroblast cell lines derived from unrelated XP-V patients with distinct mutations in pol η [28,29]. XP30RO/pol η cl5 and XP30RO/ cDNA3 are XP30RO cells that respectively contain either an expression vector containing the pol η cDNA or an empty vector [30][31][32]. All cells were grown in Dulbecco's modified Eagle medium supplemented with 10% fetal bovine serum at 37°C, 5% CO 2 and were actively growing during subsequent experiments.…”

Section: Cellsmentioning

confidence: 99%

“…XP30RO/pol η is an XP-V cell line transfected with a vector expressing wild-type pol η cDNA, while XP30RO/cDNA3 is an empty vector-treated control cell line [31,32]. As shown in Fig.…”

Section: Xp-v Cells Are Hypersensitive To Interstrand Crosslinks But mentioning

confidence: 99%

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DNA polymerase η reduces the γ-H2AX response to psoralen interstrand crosslinks in human cells

Mogi

Butcher

2008

Experimental Cell Research

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DNA interstrand crosslinks are processed by multiple mechanisms whose relationships to each other are unclear. Xeroderma pigmentosum-variant (XP-V) cells lacking DNA polymerase η are sensitive to psoralen photoadducts created under conditions favoring crosslink formation, suggesting a role for translesion synthesis in crosslink repair. Because crosslinks can lead to double strand breaks, we monitored phosphorylated H2AX (γ-H2AX), which is typically generated near double-strand breaks but also in response to single-stranded DNA, following psoralen photoadduct formation in XP-V fibroblasts to assess whether polymerase η is involved in processing crosslinks. In contrast to conditions favoring monoadducts, conditions favoring psoralen crosslinks induced γ-H2AX levels in both XP-V and nucleotide excision repair-deficient XP-A cells relative to control repair-proficient cells; ectopic expression of polymerase η in XP-V cells normalized the γ-H2AX response. In response to psoralen crosslinking, γ-H2AX as well as 53BP1 formed co-incident foci that were more numerous and intense in XP-V and XP-A cells than in controls. Psoralen photoadducts induced γ-H2AX throughout the cell cycle in XP-V cells. These results indicate that polymerase η is important in responding to psoralen crosslinks, and are consistent with a model in which nucleotide excision repair and polymerase η are involved in processing crosslinks and avoiding γ-H2AX associated with double strand breaks and single-stranded DNA in human cells.

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Section: Discussionmentioning

confidence: 99%

Section: Cellsmentioning

confidence: 99%

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DNA polymerase η reduces the γ-H2AX response to psoralen interstrand crosslinks in human cells

Mogi

Butcher

2008

Experimental Cell Research

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“…of Functional Biology (Genetic Area) and Oncology University Institute and inter-and intra-strand crosslinks. [4][5][6] The most frequently generated cisplatin-induced adducts, intra-strand guanineguanine (G-G) cross-links, can block DNA replication and transcription [6][7][8] and lead to cell cycle arrest and apoptosis. 6 Tumors can become resistant to cisplatin by a variety of processes, such as decreased uptake/influx or increased efflux of the drug; low apoptosis capacity due to hypermethylation of gene promoters; increased DNA repair activity and/or increased DNA adduct bypass activity.…”

Section: Introductionmentioning

confidence: 99%

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

et al. 2017

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Cisplatin, one of the most extensively used metallodrugs in cancer treatment, presents the important drawback of patient resistance. This resistance is the consequence of different processes including those preventing the formation of DNA adducts and/or their quick removal. Thus, a tool for the accurate detection and quantitation of cisplatin-induced adducts might be valuable for predicting patient resistance. To prove the validity of such an assumption, highly sensitive plasma mass spectrometry (ICP-MS) strategies were applied to determine DNA adduct levels and intracellular Pt concentrations. These two metal-relative parameters were combined with an evaluation of biological responses in terms of genomic stability (with the Comet assay) and cell cycle progression (by flow cytometry) in four human cell lines of different origins and cisplatin sensitivities (A549, GM04312, A2780 and A2780cis), treated with low cisplatin doses (5, 10 and 20 mM for 3 hours). Cell viability and apoptosis were determined as resistance indicators. Univariate linear regression analyses indicated that quantitation of cisplatin-induced G-G intra-strand adducts, measured 1 h after treatment, was the best predictor for viability and apoptosis in all of the cell lines. Multivariate linear regression analyses revealed that the prediction improved when the intracellular Pt content or the Comet data were included in the analysis, for all sensitive cell lines and for the A2780 and A2780cis cell lines, respectively. Thus, a reliable cisplatin resistance predictive model, which combines the quantitation of adducts by HPLC-ICP-MS, and their repair, with the intracellular Pt content and induced genomic instability, might be essential to identify early therapy failure. Significance to metallomicsKnowledge about cisplatin as a chemotherapy drug is extensive, including information about the several processes that contribute to its resistance, the main problem of using this chemical. However, this knowledge and information does not yet allow the early identification of resistant tumors/patients, one of the most desired aims of clinicians. In this work we have developed a model that might allow the early detection of chemical resistance and, more importantly, might do so mostly regardless of the resistance mechanism involved, because it determines the dynamics of adduct induction/repair, considering chemical influx/efflux and induced genomic instability.

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“…Multiple translesion DNA synthesis TLS polymerases are implicated in the lesion bypass of DNA intra-strand cross-links, including those generated by DDP. Replicative bypass of DDP adducts requires the cooperative actions of at least three TLS Pol isoforms : Pol , REV1, and Pol [7][8][9][10][11][12][13][14][15][16] . A reduction in Pol or REV1 function renders cells more sensitive to the cytotoxic effects of DDP, and also markedly decreases its mutagenicity in vitro 11 14 .…”

Section: Cis-diamminedichloroplatinummentioning

confidence: 99%

Overexpression of DNA Polymerase ζ Affects Cisplatin Resistance in Ovarian Cancer: An Immunohistochemical Study

Nagashima

Okuda

Nagatsuka

et al. 2013

Showa Univ J Med Sci

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: DNA polymerase Pol participates in translesional bypass replication. Pol has been shown to be an important contributor to cisdiamminedichloroplatinum DDP ; cisplatin -induced genomic instability and the subsequent emergence of resistance in vitro. We immunohistochemically examined the expression of Pol in ovarian cancer tissues to determine whether its expression affects the DDP resistance of human ovarian cancers and also to determine whether Pol expression is a prognostic factor for ovarian cancers. We assessed 76 archival, formalin-fixed, paraffin-embedded tissue samples obtained from patients with epithelial ovarian cancers who underwent their first operation between 2003 and 2011. An ovarian cancer tissue array was also used in this study. Immunohistochemical staining of Pol was performed using an anti-human Pol monoclonal rabbit antibody. The strength of expression of Pol was compared with the DDP resistance and clinical features of the study population. The Pol over-expression in ovarian cancer tissue which compared with epithelial cells in normal ovaries was not affected by the histological types, FIGO stage, or patient age, but Pol was significantly more overexpressed in the DDP-resistant group than in the DDP-sensitive group P 0.043 . Pol over-expression did not significantly affect the survival rate of the ovarian cancer patients ; however, the Pol positive group tended to have a poorer long-term prognosis. In conclusion, ovarian carcinoma patients with Pol over-expression are likely to be resistant to DDP, especially in cases of recurrent disease. These results confirm the previous findings in vitro, wherein Pol modulated the cytotoxicity and mutagenicity of DDP.

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A Role for Polymerase η in the Cellular Tolerance to Cisplatin-Induced Damage

Cited by 196 publications

References 35 publications

DNA polymerase η reduces the γ-H2AX response to psoralen interstrand crosslinks in human cells

DNA polymerase η reduces the γ-H2AX response to psoralen interstrand crosslinks in human cells

Cisplatin resistance in cell models: evaluation of metallomic and biological predictive biomarkers to address early therapy failure

Overexpression of DNA Polymerase ζ Affects Cisplatin Resistance in Ovarian Cancer: An Immunohistochemical Study

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