Replication gap suppression depends on the double-strand DNA binding activity of BRCA2

Domagoj Vugic, Isaac Dumoulin, Charlotte Martin, Anna Minello, Lucia Alvaro-Aranda, Jesus Gomez-Escudero, Rady Chaaban, Rana Lebdy, Catharina Nicolai, Virginie Boucherit, Cyril Ribeyre, Angelos Constantinou and Aura Carreira ()
Additional contact information
Domagoj Vugic: UMR3348
Isaac Dumoulin: UMR3348
Charlotte Martin: UMR3348
Anna Minello: UMR3348
Lucia Alvaro-Aranda: Centro de Biologia Molecular Severo Ochoa (CBMSO, CSIC-UAM)
Jesus Gomez-Escudero: Centro de Biologia Molecular Severo Ochoa (CBMSO, CSIC-UAM)
Rady Chaaban: UMR3348
Rana Lebdy: Université de Montpellier
Catharina Nicolai: UMR3348
Virginie Boucherit: UMR3348
Cyril Ribeyre: Université de Montpellier
Angelos Constantinou: Université de Montpellier
Aura Carreira: UMR3348

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36149-0

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