Journal Article Research Support, Non-U.S. Gov't Epublish 11 citations
PubMed: 36707518 DOI: 10.1038/s41467-023-36149-0
Replication gap suppression depends on the double-strand DNA binding activity of BRCA2.
Nat Commun 14(1):446
Authors: Domagoj Vugic, Isaac Dumoulin, Charlotte Martin, Anna Minello, Lucia Alvaro-Aranda, Jesus Gomez-Escudero, Rady Chaaban, Rana Lebdy, Catharina von Nicolai, Virginie Boucherit, Cyril Ribeyre, Angelos Constantinou, Aura Carreira
Affiliations
- Institut Curie, PSL Research University, CNRS, UMR3348, F-91405, Orsay, France. Paris-Saclay University CNRS, UMR3348, F-91405, Orsay, France.
- Institut Curie, PSL Research University, CNRS, UMR3348, F-91405, Orsay, France.
- Paris-Saclay University CNRS, UMR3348, F-91405, Orsay, France.
- Genome Instability and Cancer Predisposition lab, Department of Genome Dynamics and Function, Centro de Biologia Molecular Severo Ochoa (CBMSO, CSIC-UAM), Madrid, 28049, Spain.
- Institut de Génétique Humaine, CNRS, Université de Montpellier, Montpellier, France.
- Institut Curie, PSL Research University, CNRS, UMR3348, F-91405, Orsay, France.
- Paris-Saclay University CNRS, UMR3348, F-91405, Orsay, France.
- Genome Instability and Cancer Predisposition lab, Department of Genome Dynamics and Function, Centro de Biologia Molecular Severo Ochoa (CBMSO, CSIC-UAM), Madrid, 28049, Spain.
Abstract
Replication stress (RS) is a major source of genomic instability and is intrinsic to cancer cells. RS is also the consequence of chemotherapeutic drugs for treating cancer. However, adaptation to RS is also a mechanism of resistance to chemotherapy. BRCA2 deficiency results in replication stress in human cells. BRCA2 protein's main functions include DNA repair by homologous recombination (HR) both at induced DNA double-strand breaks (DSB) and spontaneous replicative lesions. At stalled replication forks, BRCA2 protects the DNA from aberrant nucleolytic degradation and is thought to limit the appearance of ssDNA gaps by arresting replication and via post-replicative HR. However, whether and how BRCA2 acts to limit the formation of ssDNA gaps or mediate their repair, remains ill-defined. Here, we use breast cancer variants affecting different domains of BRCA2 to shed light on this function. We demonstrate that the N-terminal DNA binding domain (NTD), and specifically, its dsDNA binding activity, is required to prevent and repair/fill-in ssDNA gaps upon nucleotide depletion but not to limit PARPi-induced ssDNA gaps. Thus, these findings suggest that nucleotide depletion and PARPi trigger gaps via distinct mechanisms and that the NTD of BRCA2 prevents nucleotide depletion-induced ssDNA gaps.
MeSH
Biological Science Disciplines, Stress, Physiological, Dna, Cells, Neoplasms, Genes, Brca2
Cited by
- Distinct roles of the two BRCA2 DNA-binding domains in DNA damage repair and replication fork preservation. Cell Rep, 2025
- Characterization of BRCA2 R3052Q variant in mice supports its functional impact as a low-risk variant. Cell Death Dis, 2023
- DSS1 restrains BRCA2's engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis. Nat Commun, 2024
- Positioning loss of PARP1 activity as the central toxic event in BRCA-deficient cancer. DNA Repair (Amst), 2024
- Visualization of direct and diffusion-assisted RAD51 nucleation by full-length human BRCA2 protein. Mol Cell, 2023
- BRCA2 prevents PARPi-mediated PARP1 retention to protect RAD51 filaments. Nature, 2025