Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress
| العنوان: | Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress |
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| المؤلفون: | Ida H van der Meulen-Muileman, Ellen Siebring-van Olst, Egbert F. Smit, Victor W. van Beusechem, Ilya N. Kotov, Rolf A. Stahel, Philip A. Knobel, Emanuela Felley-Bosco, Thomas M. Marti |
| المساهمون: | University of Zurich, Marti, Thomas M, Pulmonary medicine, Medical oncology laboratory, CCA - Innovative therapy |
| المصدر: | Kotov, I N, van Olst, E, Knobel, P A, van der Meulen-Muileman, I, Felley-Bosco, E, van Beusechem, V W, Smit, E F, Stahel, R A & Marti, T M 2014, ' Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress ', Molecular oncology, vol. 8, no. 8, pp. 1747-1759 . https://doi.org/10.1016/j.molonc.2014.07.008 Molecular oncology, 8(8), 1747-1759. Elsevier |
| بيانات النشر: | John Wiley and Sons Inc., 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | DNA Replication, Cancer Research, Ribonucleoside Diphosphate Reductase, DNA polymerase II, 610 Medicine & health, Eukaryotic DNA replication, DNA-Directed DNA Polymerase, DNA polymerase delta, Replication factor C, 1311 Genetics, Control of chromosome duplication, Cell Line, Tumor, Genetics, Humans, 1306 Cancer Research, Replication protein A, Research Articles, biology, Tumor Suppressor Proteins, DNA replication, General Medicine, Flow Cytometry, Molecular biology, DNA-Binding Proteins, Oncology, 1313 Molecular Medicine, 10032 Clinic for Oncology and Hematology, biology.protein, Molecular Medicine, Origin recognition complex, RNA Interference |
| الوصف: | REV3, the catalytic subunit of translesion polymerase zeta (polζ), is commonly associated with DNA damage bypass and repair. Despite sharing accessory subunits with replicative polymerase δ, very little is known about the role of polζ in DNA replication. We previously demonstrated that inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells. To reveal determinants of this sensitivity and obtain insights into the cellular function of REV3, we performed whole human genome RNAi library screens aimed at identification of synthetic lethal interactions with REV3 in A549 lung cancer cells. The top confirmed hit was RRM1, the large subunit of ribonucleotide reductase (RNR), a critical enzyme of de novo nucleotide synthesis. Treatment with the RNR-inhibitor hydroxyurea (HU) synergistically increased the fraction of REV3-deficient cells containing single stranded DNA (ssDNA) as indicated by an increase in replication protein A (RPA). However, this increase was not accompanied by accumulation of the DNA damage marker γH2AX suggesting a role of REV3 in counteracting HU-induced replication stress (RS). Consistent with a role of REV3 in DNA replication, increased RPA staining was confined to HU-treated S-phase cells. Additionally, we found genes related to RS to be significantly enriched among the top hits of the synthetic sickness/lethality (SSL) screen further corroborating the importance of REV3 for DNA replication under conditions of RS. |
| وصف الملف: | Kotov et al_Mol Onc_2014.pdf - application/pdf |
| اللغة: | English |
| تدمد: | 1574-7891 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6fe9641424a1ac3de3bf5988b6d9872c https://europepmc.org/articles/PMC5528584/ |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6fe9641424a1ac3de3bf5988b6d9872c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15747891 |
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