University of Oulu

Sachsenweger, J., Jansche, R., Merk, T. et al. ABRAXAS1 orchestrates BRCA1 activities to counter genome destabilizing repair pathways—lessons from breast cancer patients. Cell Death Dis 14, 328 (2023).

ABRAXAS1 orchestrates BRCA1 activities to counter genome destabilizing repair pathways : lessons from breast cancer patients

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Author: Sachsenweger, Juliane1,2; Jansche, Rebecca1; Merk, Tatjana1;
Organizations: 1Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany
2Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland
3Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
4Institute of Human Genetics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
5Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany
6Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
7Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.9 MB)
Persistent link:
Language: English
Published: Springer Nature, 2023
Publish Date: 2023-09-06


It has been well-established that mutations in BRCA1 and BRCA2, compromising functions in DNA double-strand break repair (DSBR), confer hereditary breast and ovarian cancer risk. Importantly, mutations in these genes explain only a minor fraction of the hereditary risk and of the subset of DSBR deficient tumors. Our screening efforts identified two truncating germline mutations in the gene encoding the BRCA1 complex partner ABRAXAS1 in German early-onset breast cancer patients. To unravel the molecular mechanisms triggering carcinogenesis in these carriers of heterozygous mutations, we examined DSBR functions in patient-derived lymphoblastoid cells (LCLs) and in genetically manipulated mammary epithelial cells. By use of these strategies we were able to demonstrate that these truncating ABRAXAS1 mutations exerted dominant effects on BRCA1 functions. Interestingly, we did not observe haploinsufficiency regarding homologous recombination (HR) proficiency (reporter assay, RAD51-foci, PARP-inhibitor sensitivity) in mutation carriers. However, the balance was shifted to use of mutagenic DSBR-pathways. The dominant effect of truncated ABRAXAS1 devoid of the C-terminal BRCA1 binding site can be explained by retention of the N-terminal interaction sites for other BRCA1-A complex partners like RAP80. In this case BRCA1 was channeled from the BRCA1-A to the BRCA1-C complex, which induced single-strand annealing (SSA). Further truncation, additionally deleting the coiled-coil region of ABRAXAS1, unleashed excessive DNA damage responses (DDRs) de-repressing multiple DSBR-pathways including SSA and non-homologous end-joining (NHEJ). Our data reveal de-repression of low-fidelity repair activities as a common feature of cells from patients with heterozygous mutations in genes encoding BRCA1 and its complex partners.

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Series: Cell death and disease
ISSN: 2041-4889
ISSN-E: 2041-4889
ISSN-L: 2041-4889
Volume: 14
Article number: 328
DOI: 10.1038/s41419-023-05845-6
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This project was supported by the International Graduate School in Molecular Medicine Ulm, Germany (to LW). JS was and RJ is a member of the International Graduate School in Molecular Medicine Ulm. RW, KP and HPe were supported by the University of Oulu and Biocenter Oulu as well as research project funding from the Finnish Cancer Foundation, the Academy of Finland, and the Sigrid Juselius Foundation to RW and KP. HPo was financially supported by grant PO 1884/2-1 (Deutsche Forschungsgemeinschaft). LW was financially supported by the German Cancer Aid, Priority Program ‘Translational Oncology’, project HerediVar´, 70114178. TM received a scholarship for Experimental Medicine by the Medical Faculty of Ulm University. BH was funded by the Else Kröner Fresenius Stiftung. 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Open Access funding enabled and organized by Projekt DEAL.
Copyright information: © The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit