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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 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity Tvůrce(i) 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)Zdroj.dok. OncoTarget. - : Impact Journals LLC - ISSN 1949-2553
Roč. 6, č. 13 (2015), s. 10746-10758Poč.str. 13 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova DNA damage response ; ubiquitin-proteasome system ; RNA interference screens ; PARP inhibitors ; CBLC Vědní obor RIV EB - Genetika a molekulární biologie CEP GA13-17555S GA ČR - Grantová agentura ČR Institucionální podpora UMG-J - RVO:68378050 UT WOS 000359006400008 DOI 10.18632/oncotarget.3628 Anotace 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. Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2016
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