Patient-derived separation-of-function mutations reveal specific role for BRCA1 coiled coil domain in genome stability.
12 affiliations
- 1Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.
- 2IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy.
- 3Doctoral School of Biology, ELTE Eötvös Loránd University, Budapest, Hungary.
- 4Molecular Medicine Division, Semmelweis University Doctoral School, Semmelweis University, Budapest, Hungary.
- 5Danish Cancer Institute, Copenhagen, Denmark.
- 6Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
- 7Department of Bioinformatics, Semmelweis University, Budapest, Hungary.
- 8Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), Pavia, Italy.
- 9Research Center One Health Ruhr, University Alliance Ruhr, Faculty of Biology, University of Duisburg-Essen, Essen, Germany.
- 10Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
- 11Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary. [email protected].
- 12National Laboratory for Drug Research and Development, Budapest, Hungary. [email protected].
Abstract
Specific inherited mutations of BRCA1 compromise homologous recombination repair and increase the risk of cancer. Here, we employ a panel of isogenic chicken DT40 cell lines for the comparative study of the main BRCA1 protein domains and of common BRCA1 founder mutations in genome stability and DNA repair. Whole genome sequencing of cell clones demonstrates that the L1407P-equivalent coiled coil domain variant is a separation-of-function mutant with an increased rate of base substitution mutagenesis but not of deletions or large-scale genomic instability, reflecting its proficiency in repairing DNA double strand breaks and promoting sister chromatid exchanges. The BRCA1 coiled coil domain mediates interaction with PALB2, and PALB2 coiled coil domain mutations also primarily affect base substitution mutagenesis. In contrast, truncating and missense mutations in the RING and BRCT domains affect all functions of BRCA1, inducing larger deletions and rearrangements typical of BRCA1 loss. PARP inhibitor sensitivity is marginal in the coiled coil domain mutants, instead it correlates with deletion mutagenesis, degradation of stalled replication forks, and impaired RAD51 loading following topoisomerase I inhibition. Our results suggest a specific function for the BRCA1-PALB2 interaction in promoting error-free DNA damage bypass as an alternative to mutagenic translesion DNA synthesis.
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BibTeX
@article{szikriszt2026patientderived,
title = {{Patient-derived separation-of-function mutations reveal specific role for BRCA1 coiled coil domain in genome stability.}},
author = {Bernadett Szikriszt and Eszter Németh and Bayejid Hosen and Michał Krawczyk and Regina Martinek and Bendegúz Szabó and Ádám Póti and Zoltán Szeltner and György Várady and Zsófia Sztupinszki and Zoltan Szallasi and Dana Branzei and Andrea L Richardson and Dávid Szüts},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77330-5},
url = {https://europepmc.org/article/MED/42907458},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Patient-derived separation-of-function mutations reveal specific role for BRCA1 coiled coil domain in genome stability.
AU - Bernadett Szikriszt
AU - Eszter Németh
AU - Bayejid Hosen
AU - Michał Krawczyk
AU - Regina Martinek
AU - Bendegúz Szabó
AU - Ádám Póti
AU - Zoltán Szeltner
AU - György Várady
AU - Zsófia Sztupinszki
AU - Zoltan Szallasi
AU - Dana Branzei
AU - Andrea L Richardson
AU - Dávid Szüts
PY - 2026
DA - 2026/09/22
JO - Nature communications
DO - 10.1038/s41467-026-77330-5
UR - https://europepmc.org/article/MED/42907458
AB - Specific inherited mutations of BRCA1 compromise homologous recombination repair and increase the risk of cancer. Here, we employ a panel of isogenic chicken DT40 cell lines for the comparative study of the main BRCA1 protein domains and of common BRCA1 founder mutations in genome stability and DNA repair. Whole genome sequencing of cell clones demonstrates that the L1407P-equivalent coiled coil domain variant is a separation-of-function mutant with an increased rate of base substitution mutagenesis but not of deletions or large-scale genomic instability, reflecting its proficiency in repairing DNA double strand breaks and promoting sister chromatid exchanges. The BRCA1 coiled coil domain mediates interaction with PALB2, and PALB2 coiled coil domain mutations also primarily affect base substitution mutagenesis. In contrast, truncating and missense mutations in the RING and BRCT domains affect all functions of BRCA1, inducing larger deletions and rearrangements typical of BRCA1 loss. PARP inhibitor sensitivity is marginal in the coiled coil domain mutants, instead it correlates with deletion mutagenesis, degradation of stalled replication forks, and impaired RAD51 loading following topoisomerase I inhibition. Our results suggest a specific function for the BRCA1-PALB2 interaction in promoting error-free DNA damage bypass as an alternative to mutagenic translesion DNA synthesis.
SN - 2041-1723
ER -