University of Oulu

Classen S, Rahlf E, Jungwirth J, Albers N, Hebestreit LP, Zielinski A, Poole L, Groth M, Koch P, Liehr T, et al. Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance. International Journal of Molecular Sciences. 2022; 23(21):13363.

Partial reduction in BRCA1 gene dose modulates DNA replication stress level and thereby contributes to sensitivity or resistance

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Author: Classen, Sandra1; Rahlf, Elena1; Jungwirth, Johannes2;
Organizations: 1Laboratory of Radiobiology and Experimental Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
2Project Group Biochemistry, Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany
3CF Next-Generation Sequencing, Leibniz Institute on Aging-Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany
4CF Life Science Computing, Leibniz Institute on Aging-Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany
5Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Am Klinikum 1, 07747 Jena, Germany
6OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, PF 41, 01307 Dresden, Germany
7National Center for Tumor Diseases, Partner Site Dresden: German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
8Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, PF 50, 01307 Dresden, Germany
9Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Bautzner Landstr. 400, 01328 Dresden, Germany
10German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69192 Heidelberg, Germany
11Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
12Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.1 MB)
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Language: English
Published: Multidisciplinary Digital Publishing Institute, 2022
Publish Date: 2023-06-30


BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.

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Series: International journal of molecular sciences
ISSN: 1661-6596
ISSN-E: 1422-0067
ISSN-L: 1661-6596
Volume: 23
Issue: 21
Article number: 13363
DOI: 10.3390/ijms232113363
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This research was funded by DFG Grant BO1868/5 and PO1884/2-1, as well as BMBF grants 02NUK055A, 02NUK055B and 02NUK055C and Hamburger Krebsgesellschaft e.V. 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.
Copyright information: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (