Vaclova, T., Woods, N. T., Megias, D., Gomez-Lopez, S., Setien, F., Bueno, J. M. G., Macias, J. A., Barroso, A., Urioste, M., Esteller, M., Monteiro, A. N. A., Benitez, J., Osorio, A. (2016) Germline missense pathogenic variants in the BRCA1 BRCT domain, p.Gly1706Glu and p.Ala1708Glu, increase cellular sensitivity to PARP inhibitor olaparib by a dominant negative effect. HUMAN MOLECULAR GENETICS, 25 (24). pp. 5287-5299. ISSN 0964-6906

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Abstract

BRCA1-deficient cells show defects in DNA repair and rely on other members of the DNA repair machinery, which makes them sensitive to PARP inhibitors (PARPi). Although carrying a germline pathogenic variant in BRCA1/2 is the best determinant of response to PARPi, a significant percentage of the patients do not show sensitivity and/or display increased toxicity to the agent. Considering previously suggested mutation-specific BRCA1 haploinsufficiency, we aimed to investigate whether there are any differences in cellular response to PARPi olaparib depending on the BRCA1 mutation type. Lymphoblastoid cell lines derived from carriers of missense pathogenic variants in the BRCA1 BRCT domain (c.5117G> A, p.Gly1706Glu and c.5123C> A, p.Ala1708Glu) showed higher sensitivity to olaparib than cells with truncating variants or wild types (WT). Response to olaparib depended on a basal PARP enzymatic activity, but did not correlate with PARP1 expression. Interestingly, cellular sensitivity to the agent was associated with the level of BRCA1 recruitment into cH2AX foci, being the lowest in cells with missense variants. Since these variants lead to partially stable protein mutants, we propose a model in which the mutant protein acts in a dominant negative manner on the WT BRCA1, impairing the recruitment of BRCA1 into DNA damage sites and, consequently, increasing cellular sensitivity to PARPi. Taken together, our results indicate that carriers of different BRCA1 mutations could benefit from olaparib in a distinct way and show different toxicities to the agent, which could be especially relevant for a potential future use of PARPi as prophylactic agents in BRCA1 mutation carriers.

Item Type:	Article
All Authors:	Vaclova, T., Woods, N. T., Megias, D., Gomez-Lopez, S., Setien, F., Bueno, J. M. G., Macias, J. A., Barroso, A., Urioste, M., Esteller, M., Monteiro, A. N. A., Benitez, J., Osorio, A.
Additional Information:	ISI Document Delivery No.: EP0FZ Times Cited: 0 Cited Reference Count: 48 Vaclova, Tereza Woods, Nicholas T. Megias, Diego Gomez-Lopez, Sergio Setien, Fernando Garcia Bueno, Jose Maria Antonio Macias, Jose Barroso, Alicia Urioste, Miguel Esteller, Manel Monteiro, Alvaro N. A. Benitez, Javier Osorio, Ana Osorio, Ana/I-4324-2014 Osorio, Ana/0000-0001-8124-3984 Spanish Ministry of Economy and Competitiveness (MINECO) [SAF2014-57680-R]; Spanish Network on Rare Diseases (CIBERER); NIH [CA116167]; Florida Breast Cancer Foundation The study was funded by the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Network on Rare Diseases (CIBERER). This work was partially supported by NIH U01 award CA116167 and a grant from the Florida Breast Cancer Foundation. 0 OXFORD UNIV PRESS OXFORD HUM MOL GENET
Uncontrolled Keywords:	SUSCEPTIBILITY GENE BRCA1 SEROUS OVARIAN-CANCER POLY(ADP-RIBOSE) POLYMERASE BREAST-CANCER GENOMIC INSTABILITY MUTATION CARRIERS DNA-REPAIR OPEN-LABEL RESISTANCE EXPRESSION
Research teams:	ICR divisions > Breast Cancer Research > Complex Trait Genetics
Depositing User:	Barry Jenkins
Date Deposited:	12 May 2017 13:54
Last Modified:	12 May 2017 13:54
URI:	http://publications.icr.ac.uk/id/eprint/15914

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