BRCA1 mislocalization leads to aberrant DNA damage response in heterozygous ABRAXAS1 mutation carrier cells. (20th October 2019)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Human molecular genetics. Volume 28:Number 24(2019)
• Page Start: 4148
• Page End: 4160
• Publication Date: 2019-10-20
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddz252
• Languages: English
• ISSNs: 0964-6906

Abstract

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. Graphical Abstract: