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dc.contributor.authorMeyer, Stefan
dc.contributor.authorStevens, A
dc.contributor.authorParedes, R
dc.contributor.authorSchneider, M
dc.contributor.authorWalker, M
dc.contributor.authorWilliamson, A
dc.contributor.authorGonzalez-Sanchez, M
dc.contributor.authorSmetsers, S
dc.contributor.authorDalal, V
dc.contributor.authorTeng, H
dc.contributor.authorWhite, D
dc.contributor.authorTaylor, S
dc.contributor.authorMuter, J
dc.contributor.authorPierce, A
dc.contributor.authorde Leonibus, C
dc.contributor.authorRockx, D
dc.contributor.authorRooimans, M
dc.contributor.authorSpooncer, E
dc.contributor.authorStauffer, S
dc.contributor.authorBiswas, K
dc.contributor.authorGodthelp, B
dc.contributor.authorDorsman, J
dc.contributor.authorClayton, P
dc.contributor.authorSharan, S
dc.contributor.authorWhetton, A
dc.date.accessioned2017-07-13T11:03:50Z
dc.date.available2017-07-13T11:03:50Z
dc.date.issued2017-06-15
dc.identifier.citationAcquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption. 2017, 8 (6):e2875 Cell Death Disen
dc.identifier.issn2041-4889
dc.identifier.pmid28617445
dc.identifier.doi10.1038/cddis.2017.264
dc.identifier.urihttp://hdl.handle.net/10541/620453
dc.description.abstractBRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2(ΔE5+7)), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the 'BRCAness' profile.
dc.language.isoenen
dc.rightsArchived with thanks to Cell death & diseaseen
dc.titleAcquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption.en
dc.typeArticleen
dc.contributor.departmentStem Cell &Leukaemia Proteomics Laboratory, Manchester Cancer Research Centre, Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine & Health, University of Manchester, Manchesteren
dc.identifier.journalCell Death & Diseaseen
refterms.dateFOA2018-12-17T15:00:57Z
html.description.abstractBRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2(ΔE5+7)), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the 'BRCAness' profile.


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