Mechanism of cell killing after ionizing radiation by a dominant negative DNA polymerase beta

Neijenhuis, Sari; Verwijs-Janssen, Manon; Kasten-Pisula, Ulla; Rumping, Gaby; Borgmann, Kerstin; Dikomey, Ekkehard; Begg, Adrian C.; Vens, Conchita

doi:10.1016/j.dnarep.2008.11.008

Cited by 33 publications

(20 citation statements)

References 48 publications

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“…This inhibitor was previously shown to effectively inhibit NHEJ and sensitize cells to IR (24,25). As previously shown (17,20), A549-polβ-Δ was more radiosensitive compared with A549-LZRS. Incubation with NU7026 for 24 hours did not result in significant toxicity: Exposure to 5 μmol/L NU7026 resulted in an average of 83% and 91% survival compared with untreated A549-LZRS and A549-polβ-Δ cells, respectively.…”

Section: Radiosensitization Does Not Results From Polβ-δ Interference supporting

confidence: 62%

“…In cells expressing this truncated protein (polβ-Δ), we observed increased induction of chromosome and chromatid-type aberrations after IR, indicating formation of secondary DSBs (17). Our data indicated that these arose partly during repair of IR-specific clustered damage and partly during replication.…”

Section: Introductionmentioning

confidence: 57%

“…We have previously shown that expression of the dominantnegative polβ-Δ protein interferes with BER after IR and results in increased formation of residual double-strand breaks (DSB) as indicated by an increase in chromosome and chromatid aberrations (17). Here, we analyzed γH2AX foci induction at earlier time points after radiation.…”

Section: Polβ-δ Expression Leads To a Transient Increase In γH2ax Focmentioning

confidence: 99%

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Targeted Radiosensitization of Cells Expressing Truncated DNA Polymerase β

et al. 2010

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Ionizing radiation (IR) is an effective anticancer treatment, although failures still occur. To improve radiotherapy, tumor-targeted strategies are needed to increase radiosensitivity of tumor cells, without influencing normal tissue radiosensitivity. Base excision repair (BER) and single-strand break repair (SSBR) contribute to the determination of sensitivity to IR. A crucial protein in BER/SSBR is DNA polymerase β (polβ). Aberrant polβ expression is commonly found in human tumors and leads to inhibition of BER. Here, we show that truncated polβ variant (polβ-Δ)-expressing cells depend on homologous recombination (HR) for survival after IR, indicating that a considerable fraction of polβ-Δ-induced lesions are subject to repair by HR. Increased sensitization was found not to result from involvement in DNA-dependent protein kinase-dependent nonhomologous end joining, the other major double-strand break repair pathway. Caffeine and the ATM inhibitor Ku55933 cause polβ-Δ-dependent radiosensitization. Consistent with the observed HR dependence and the known HR-modulating activity of ATM, polβ-Δ-expressing cells showed increased radiosensitization after BRCA2 knockdown that is absent under ATM-inhibited conditions. Our data suggest that treatment with HR modulators is a promising therapeutic strategy for exploiting defects in the BER/SSBR pathway in human tumors.

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Section: Radiosensitization Does Not Results From Polβ-δ Interference supporting

confidence: 62%

Section: Introductionmentioning

confidence: 57%

Section: Polβ-δ Expression Leads To a Transient Increase In γH2ax Focmentioning

confidence: 99%

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Targeted Radiosensitization of Cells Expressing Truncated DNA Polymerase β

et al. 2010

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“…DNA DSBs were quantified by constant-field gel electrophoresis as described (20). In short, HAP1 cells were treated with doxorubicin or Etoposide for 2 hours.…”

Section: Constant-field Gel Electrophoresismentioning

confidence: 99%

Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer

et al. 2015

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The topoisomerase II poisons doxorubicin and etoposide constitute longstanding cornerstones of chemotherapy. Despite their extensive clinical use, many patients do not respond to these drugs. Using a genome-wide gene knockout approach, we identified Keap1, the SWI/SNF complex, and C9orf82 (CAAP1) as independent factors capable of driving drug resistance through diverse molecular mechanisms, all converging on the DNA double-strand break (DSB) and repair pathway. Loss of Keap1 or the SWI/SNF complex inhibits generation of DSB by attenuating expression and activity of topoisomerase IIa, respectively, where-

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“…Polβ is also involved in the meiotic recombination [24] and the repair of breaks in doublestranded DNA through the process of nonhomologous end joining [25]. There are also studies that have revealed that polβ plays an important role in DNA single-strand breaks (SSB) resulting from rays and akylating agents [26][27][28]. Polβ expression is increased in many cancer cells [29].…”

Section: Introductionmentioning

confidence: 99%

MiR-499 Enhances the Cisplatin Sensitivity of Esophageal Carcinoma Cell Lines by Targeting DNA Polymerase β

Wang

Jiao

Zang

et al. 2015

Cell Physiol Biochem

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Background: Human DNA polymerase β (DNA polymerase β, polβ) is a small monomeric protein essential for short-patch base excision repair (BER). It plays an important role in regulating the sensitivity of tumor cells to chemotherapy. Methods: Luciferase reporter and western blot assays were used to determine whether polβ is a major target of miR-499. CCK-8, colony-forming survival and in vivo tumor growth assays were conducted to evaluate if miR-499 can potentially enhance the cisplatin sensitivity and therefore inhibit the proliferation of esophageal cancer (EC) cells. Flow cytometry and immunofluorescence microscopy assays were performed to evaluate whether miR-499 enhance the cisplatin sensitivity and the corresponding apoptosis in EC cells. Results: polβ was pinpointed as a target gene of miR-499. Additionally, we identified that miR-499 can enhance cisplatin's function of inhibiting proliferation and of promoting apoptosis in EC9706 and KYSE30 cell lines. Conclusions: We first investigated whether miR-499 modulates polβ, and observed the influence of miR-499 up-regulation on the sensitivity of EC cell lines to cisplatin treatment. Our study paves the way for more insightful understanding and application of chemotherapy in esophageal cancer in the future.

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Mechanism of cell killing after ionizing radiation by a dominant negative DNA polymerase beta

Cited by 33 publications

References 48 publications

Targeted Radiosensitization of Cells Expressing Truncated DNA Polymerase β

Targeted Radiosensitization of Cells Expressing Truncated DNA Polymerase β

Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer

MiR-499 Enhances the Cisplatin Sensitivity of Esophageal Carcinoma Cell Lines by Targeting DNA Polymerase β

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