BRCA1 mislocalization leads to aberrant DNA damage response in heterozygous <em>ABRAXAS1</em> 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 (2019-10-20)
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
© 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.
https://creativecommons.org/licenses/by-nc/4.0/
https://urn.fi/URN:NBN:fi-fe202003128097
Tiivistelmä
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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