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Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity
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SYSNO ASEP 0455799 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity Author(s) Frankum, J. (GB)
Moudrý, P. (DK)
Brough, R. (DK)
Hodný, Zdeněk (UMG-J) RID
Ashworth, A. (DK)
Bártek, Jiří (UMG-J) RID
Lord, C.J. (DK)Source Title OncoTarget. - : Impact Journals LLC - ISSN 1949-2553
Roč. 6, č. 13 (2015), s. 10746-10758Number of pages 13 s. Language eng - English Country US - United States Keywords DNA damage response ; ubiquitin-proteasome system ; RNA interference screens ; PARP inhibitors ; CBLC Subject RIV EB - Genetics ; Molecular Biology R&D Projects GA13-17555S GA ČR - Czech Science Foundation (CSF) Institutional support UMG-J - RVO:68378050 UT WOS 000359006400008 DOI 10.18632/oncotarget.3628 Annotation Based on a series of basic, preclinical and clinical studies, the Poly (ADP-ribose) Polymerase 1 (PARP1) inhibitor, olaparib, has recently been approved for use in ovarian cancer patients with BRCA1 or BRCA2 mutations. By identifying novel predictive biomarkers of tumour cell sensitivity to olaparib, it is possible that the utility of PARP inhibitors could be extended beyond this patient subgroup. Many of the known genetic determinants of PARP inhibitor response have key roles in DNA damage response (DDR) pathways. Although protein ubiquitylation is known to play an important role in regulating the DDR, the exact mechanisms by which this occurs are not fully understood. Using two parallel RNA interference-based screening approaches, we identified the E3 ubiquitin ligase, CBLC, as a candidate biomarker of response to olaparib. We validated this observation by demonstrating that silencing of CBLC causes increased sensitivity to olaparib in breast cancer cell line models and that defective homologous recombination (HR) DNA repair is the likely cause. This data provides an example of how defects in the ubiquitin machinery have the potential to influence the response of tumour cells to PARP inhibitors. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2016
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