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Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity
- 1.0455799 - ÚMG 2016 RIV US eng J - Journal Article
Frankum, J. - Moudrý, P. - Brough, R. - Hodný, Zdeněk - Ashworth, A. - Bártek, Jiří - Lord, C.J.
Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity.
OncoTarget. Roč. 6, č. 13 (2015), s. 10746-10758. ISSN 1949-2553
R&D Projects: GA ČR GA13-17555S
EU Projects: European Commission HEALTH-F2-2010-259893
Grant - others:Lundbeck Foundation(DK) R93-A8990; Danish Council for Independent Research(DK) DFF-1331-00262
Institutional support: RVO:68378050
Keywords : DNA damage response * ubiquitin-proteasome system * RNA interference screens * PARP inhibitors * CBLC
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 5.008, year: 2015
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.
Permanent Link: http://hdl.handle.net/11104/0256416
Number of the records: 1