2. Academic Validation
  3. Mechanism of BRCA1-BARD1 function in DNA end resection and DNA protection

Mechanism of BRCA1-BARD1 function in DNA end resection and DNA protection

  • Nature. 2024 Oct;634(8033):492-500. doi: 10.1038/s41586-024-07909-9.
Ilaria Ceppi # 1,  Maria Rosaria Dello Stritto # 1,  Martin Mütze 2,  Stefan Braunshier 1,  Valentina Mengoli 1,  Giordano Reginato 1,  Hồ Mỹ Phúc Võ 3 4,  Sonia Jimeno 5 6,  Ananya Acharya 1,  Megha Roy 1,  Aurore Sanchez 1 7,  Swagata Halder 1 8,  Sean Michael Howard 1 9,  Raphaël Guérois 10,  Pablo Huertas 5 6,  Sylvie M Noordermeer 3 4,  Ralf Seidel 2,  Petr Cejka 11
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland.
  • 2 Peter Debye Institute for Soft Matter Physics, Universität Leipzig, Leipzig, Germany.
  • 3 Leiden University Medical Center, Leiden, the Netherlands.
  • 4 Oncode Institute, Utrecht, the Netherlands.
  • 5 Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
  • 6 Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, Spain.
  • 7 Institut Curie, Paris Sciences and Lettres University, Sorbonne Université, CNRS UMR 3244, Dynamics of Genetic Information, Paris, France.
  • 8 Biological Systems Engineering, Plaksha University, Mohali, India.
  • 9 Department of Mechanical and Biomedical Engineering, Boise State University, Boise, ID, USA.
  • 10 Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Energie Atomique, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France.
  • 11 Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland. petr.cejka@irb.usi.ch.
  • # Contributed equally.
PMID: 39261728 DOI: 10.1038/s41586-024-07909-9
Abstract

DNA double-strand break (DSB) repair by homologous recombination is initiated by DNA end resection, a process involving the controlled degradation of the 5'-terminated strands at DSB sites1,2. The breast Cancer suppressor BRCA1-BARD1 not only promotes resection and homologous recombination, but it also protects DNA upon replication stress1,3-9. BRCA1-BARD1 counteracts the anti-resection and pro-non-homologous end-joining factor 53BP1, but whether it functions in resection directly has been unclear10-16. Using purified recombinant proteins, we show here that BRCA1-BARD1 directly promotes long-range DNA end resection pathways catalysed by the EXO1 or DNA2 nucleases. In the DNA2-dependent pathway, BRCA1-BARD1 stimulates DNA unwinding by the Werner or Bloom helicase. Together with MRE11-RAD50-NBS1 and phosphorylated CtIP, BRCA1-BARD1 forms the BRCA1-C complex17,18, which stimulates resection synergistically to an even greater extent. A mutation in phosphorylated CtIP (S327A), which disrupts its binding to the BRCT repeats of BRCA1 and hence the integrity of the BRCA1-C complex19-21, inhibits resection, showing that BRCA1-C is a functionally integrated ensemble. Whereas BRCA1-BARD1 stimulates resection in DSB repair, it paradoxically also protects replication forks from unscheduled degradation upon stress, which involves a homologous recombination-independent function of the recombinase RAD51 (refs. 4-6,8). We show that in the presence of RAD51, BRCA1-BARD1 instead inhibits DNA degradation. On the basis of our data, the presence and local concentration of RAD51 might determine the balance between the pronuclease and the DNA protection functions of BRCA1-BARD1 in various physiological contexts.

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