University of Oulu

Muthiah Bose, Juliane Sachsenweger, Niina Laurila, Ann Christin Parplys, Jonas Willmann, Johannes Jungwirth, Marco Groth, Katrin Rapakko, Pentti Nieminen, Thomas W P Friedl, Lisa Heiserich, Felix Meyer, Hanna Tuppurainen, Hellevi Peltoketo, Heli Nevanlinna, Katri Pylkäs, Kerstin Borgmann, Lisa Wiesmüller, Robert Winqvist, Helmut Pospiech, BRCA1 mislocalization leads to aberrant DNA damage response in heterozygous ABRAXAS1 mutation carrier cells, Human Molecular Genetics, Volume 28, Issue 24, 15 December 2019, Pages 4148–4160, https://doi.org/10.1093/hmg/ddz252

BRCA1 mislocalization leads to aberrant DNA damage response in heterozygous ABRAXAS1 mutation carrier cells

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Author: Bose, Muthiah1; Sachsenweger, Juliane2,1; Laurila, Niina1;
Organizations: 1Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu and NordLab Oulu, 90220 Oulu, Finland
2Department of Obstetrics and Gynecology, Ulm University, 89075 Ulm, Germany
3Laboratory of Radiobiology and Experimental Radiooncology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
4Project group Biochemistry, Leibniz Institute on Aging – Fritz Lipmann Institute, 07745 Jena, Germany
5Core Facility DNA Sequencing, Leibniz Institute on Aging–Fritz Lipmann Institute, 07745 Jena, Germany
6Laboratory of Genetics, Northern Finland Laboratory Centre NordLab Oulu, 90220 Oulu, Finland
7Department of Medical Informatics and Statistics, University of Oulu, 90220 Oulu, Finland
8Medipan GmbH, 15827 Dahlewitz/Berlin, Germany
9Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, 00029 Helsinki, Finland
10Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90220 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.5 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe202003128097
Language: English
Published: Oxford University Press, 2019
Publish Date: 2020-03-12
Description:

Abstract

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.

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Series: Human molecular genetics
ISSN: 0964-6906
ISSN-E: 1460-2083
ISSN-L: 0964-6906
Volume: 28
Issue: 24
Pages: 4148 - 4160
DOI: 10.1093/hmg/ddz252
OADOI: https://oadoi.org/10.1093/hmg/ddz252
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
1184 Genetics, developmental biology, physiology
Subjects:
Funding: Academy of Finland (Grant number 122715 and Center of Excellence Grant number 251314), the Finnish Cancer Foundation, the Sigrid Jusélius Foundation, the Cancer Fund of Northern Finland, the University of Oulu, the University of Oulu Support Foundation, the University of Oulu Graduate School, the Oulu University Hospital, the Orion-Farmos Research Foundation, the Ida Montin Foundation, K. Albin Johansson Foundation, the German Federal Office for Radiation Protection (UFA Grant 3610S30016), the German Federal Ministry of Education and Research (BMBF Grants 02NUK032 and 02NUK035B), the Hamburger Krebsgesellschaft e.V. and the International Graduate School in Molecular Medicine Ulm, Germany. The Fritz Lipmann Institute is a member of the Science Association ‘Gottfried Wilhelm Leibniz’ (WGL) and financially supported by the Federal Government of Germany and the State of Thuringia.
Academy of Finland Grant Number: 122715
251314
Detailed Information: 122715 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2019. Published by Oxford University Press.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.
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