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

Autor: Ceppi I; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland., Dello Stritto MR; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland., Mütze M; Peter Debye Institute for Soft Matter Physics, Universität Leipzig, Leipzig, Germany., Braunshier S; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland., Mengoli V; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland., Reginato G; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland., Võ HMP; Leiden University Medical Center, Leiden, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Jimeno S; Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.; Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, Spain., Acharya A; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland., Roy M; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland., Sanchez A; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland.; Institut Curie, Paris Sciences and Lettres University, Sorbonne Université, CNRS UMR 3244, Dynamics of Genetic Information, Paris, France., Halder S; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland.; Biological Systems Engineering, Plaksha University, Mohali, India., Howard SM; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland.; Department of Mechanical and Biomedical Engineering, Boise State University, Boise, ID, USA., Guérois R; Institute for Integrative Biology of the Cell (I2BC), Commissariat à l'Energie Atomique, CNRS, Université Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France., Huertas P; Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.; Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Sevilla, Spain., Noordermeer SM; Leiden University Medical Center, Leiden, the Netherlands.; Oncode Institute, Utrecht, the Netherlands., Seidel R; Peter Debye Institute for Soft Matter Physics, Universität Leipzig, Leipzig, Germany., Cejka P; Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Bellinzona, Switzerland. petr.cejka@irb.usi.ch.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Oct; Vol. 634 (8033), pp. 492-500. Date of Electronic Publication: 2024 Sep 11.
DOI: 10.1038/s41586-024-07909-9
Abstrakt: 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 sites 1,2 . The breast cancer suppressor BRCA1-BARD1 not only promotes resection and homologous recombination, but it also protects DNA upon replication stress 1,3-9 . BRCA1-BARD1 counteracts the anti-resection and pro-non-homologous end-joining factor 53BP1, but whether it functions in resection directly has been unclear 10-16 . 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 complex 17,18 , 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 complex 19-21 , 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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