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BRCA1 mislocalization leads to aberrant DNA damage response in heterozygous ABRAXAS1 mutation carrier cells.
Bose, Muthiah; Sachsenweger, Juliane; Laurila, Niina; Parplys, Ann Christin; Willmann, Jonas; Jungwirth, Johannes; Groth, Marco; Rapakko, Katrin; Nieminen, Pentti; Friedl, Thomas W P; Heiserich, Lisa; Meyer, Felix; Tuppurainen, Hanna; Peltoketo, Hellevi; Nevanlinna, Heli; Pylkäs, Katri; Borgmann, Kerstin; Wiesmüller, Lisa; Winqvist, Robert; Pospiech, Helmut.
Afiliação
  • Bose M; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu and NordLab Oulu, 90220 Oulu, Finland.
  • Sachsenweger J; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu and NordLab Oulu, 90220 Oulu, Finland.
  • Laurila N; Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany.
  • Parplys AC; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu and NordLab Oulu, 90220 Oulu, Finland.
  • Willmann J; Laboratory of Radiobiology and Experimental Radiooncology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Jungwirth J; Laboratory of Radiobiology and Experimental Radiooncology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Groth M; Project group Biochemistry, Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany.
  • Rapakko K; Core Facility DNA Sequencing, Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany.
  • Nieminen P; Laboratory of Genetics, Northern Finland Laboratory Centre NordLab Oulu, 90220 Oulu, Finland.
  • Friedl TWP; Department of Medical Informatics and Statistics, University of Oulu, 90220 Oulu, Finland.
  • Heiserich L; Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany.
  • Meyer F; Medipan GmbH, 15827 Dahlewitz/Berlin, Germany.
  • Tuppurainen H; Laboratory of Radiobiology and Experimental Radiooncology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Peltoketo H; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu and NordLab Oulu, 90220 Oulu, Finland.
  • Nevanlinna H; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu and NordLab Oulu, 90220 Oulu, Finland.
  • Pylkäs K; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, 00029 Helsinki, Finland.
  • Borgmann K; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu and NordLab Oulu, 90220 Oulu, Finland.
  • Wiesmüller L; Laboratory of Radiobiology and Experimental Radiooncology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • Winqvist R; Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany.
  • Pospiech H; Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu and NordLab Oulu, 90220 Oulu, Finland.
Hum Mol Genet ; 28(24): 4148-4160, 2019 12 15.
Article em En | MEDLINE | ID: mdl-31630195
Whilst heterozygous germline mutations in the ABRAXAS1 gene have been associated with a hereditary predisposition to breast cancer, their effect on promoting tumourigenesis at the cellular level has not been explored. Here, we demonstrate in patient-derived cells that the Finnish ABRAXAS1 founder mutation (c.1082G > A, Arg361Gln), even in the heterozygous state leads to decreased BRCA1 protein levels as well as reduced nuclear localization and foci formation of BRCA1 and CtIP. This causes disturbances in basal BRCA1-A complex localization, which is reflected by a restraint in error-prone DNA double-strand break repair pathway usage, attenuated DNA damage response and deregulated G2-M checkpoint control. The current study clearly demonstrates how the Finnish ABRAXAS1 founder mutation acts in a dominant-negative manner on BRCA1 to promote genome destabilization in heterozygous carrier cells.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Proteínas de Transporte / Mutação em Linhagem Germinativa / Proteína BRCA1 / Reparo do DNA / Quebras de DNA de Cadeia Dupla Idioma: En Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Finlândia

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Proteínas de Transporte / Mutação em Linhagem Germinativa / Proteína BRCA1 / Reparo do DNA / Quebras de DNA de Cadeia Dupla Idioma: En Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Finlândia