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

Ilaria Ceppi, Maria Rosaria Dello Stritto, Martin Mütze, Stefan Braunshier, Valentina Mengoli, Giordano Reginato, Hồ Mỹ Phúc Võ, Sonia Jimeno, Ananya Acharya, Megha Roy, Aurore Sanchez, Swagata Halder, Sean Michael Howard, Raphaël Guérois, Pablo Huertas, Sylvie M. Noordermeer, Ralf Seidel and Petr Cejka ()
Additional contact information
Ilaria Ceppi: Faculty of Biomedical Sciences
Maria Rosaria Dello Stritto: Faculty of Biomedical Sciences
Martin Mütze: Universität Leipzig
Stefan Braunshier: Faculty of Biomedical Sciences
Valentina Mengoli: Faculty of Biomedical Sciences
Giordano Reginato: Faculty of Biomedical Sciences
Hồ Mỹ Phúc Võ: Leiden University Medical Center
Sonia Jimeno: Universidad de Sevilla
Ananya Acharya: Faculty of Biomedical Sciences
Megha Roy: Faculty of Biomedical Sciences
Aurore Sanchez: Faculty of Biomedical Sciences
Swagata Halder: Faculty of Biomedical Sciences
Sean Michael Howard: Faculty of Biomedical Sciences
Raphaël Guérois: Université Paris-Saclay
Pablo Huertas: Universidad de Sevilla
Sylvie M. Noordermeer: Leiden University Medical Center
Ralf Seidel: Universität Leipzig
Petr Cejka: Faculty of Biomedical Sciences

Nature, 2024, vol. 634, issue 8033, 492-500

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07909-9

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