BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis

Daniel Salas-Lloret, Néstor García-Rodríguez, Emily Soto-Hidalgo, Lourdes González-Vinceiro, Carmen Espejo-Serrano, Lisanne Giebel, María Luisa Mateos-Martín, Arnoud H. Ru, Peter A. Veelen, Pablo Huertas, Alfred C. O. Vertegaal and Román González-Prieto ()
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Daniel Salas-Lloret: Leiden University Medical Centre
Néstor García-Rodríguez: Universidad de Sevilla
Emily Soto-Hidalgo: Universidad de Sevilla-CSIC-Universidad Pablo de Olavide-Junta de Andalucía
Lourdes González-Vinceiro: Universidad de Sevilla-CSIC-Universidad Pablo de Olavide-Junta de Andalucía
Carmen Espejo-Serrano: Universidad de Sevilla-CSIC-Universidad Pablo de Olavide-Junta de Andalucía
Lisanne Giebel: Leiden University Medical Centre
María Luisa Mateos-Martín: IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Proteomics Facility
Arnoud H. Ru: Leiden University Medical Center
Peter A. Veelen: Leiden University Medical Center
Pablo Huertas: Universidad de Sevilla
Alfred C. O. Vertegaal: Leiden University Medical Centre
Román González-Prieto: Leiden University Medical Centre

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial. Here, we observe that the BRCA1/BARD1 ubiquitin E3 activity is not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identify substrates for BRCA1/BARD1. We find that PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18. PCNA ubiquitination by BRCA1/BARD1 avoids the formation of ssDNA gaps during DNA replication and promotes continuous DNA synthesis. These results provide additional insight about the importance of BRCA1/BARD1 E3 activity in Homologous Recombination.

Date: 2024
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DOI: 10.1038/s41467-024-48427-6

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