Biology subjects

Boucherit, V.

Publications and source records attributed to Boucherit, V..

3 recordsLinked to original sources

bioRxiv2026

A single H2A variant prevents genome instability through piRNAs biogenesis and replication stress control.

Transposable elements (TEs) pose a major threat to genome integrity in the germline, where the piRNA pathway ensures heritable TEs silencing. How the chromatin environment that enables piRNA biogenesis is first established during oogenesis remains unclear. Here, we identify the histone variant His2Av, the single H2A variant in Drosophila combining H2A.Z (transcriptional) and H2A.X (DNA repair) features, as a critical regulator of the earliest steps of piRNA pathway activation. Germline-specific depletion of His2Av disrupts transcription of piRNA pathway genes, abolishes dual-strand piRNA cluster transcription, and triggers strong TEs derepression. These defects are associated with loss of Rhino recruitment despite intact H3K9me3, suggesting that His2Av contributes to the establishment of a specialized heterochromatin permissive for noncanonical piRNA cluster transcription. His2Av depletion also causes DNA damage, replication stress, and activation of Chk2- and Claspin-dependent checkpoints, leading to oogenesis arrest. Remarkably, overexpression of RNase H, but not a catalytic-dead variant, robustly rescues oocyte development, suggesting that replication stress is a major source of DNA damage in His2Av mutants. Finally, using a separation-of-function approach with a C-terminal truncation inhibiting H2A.X-like activity, we show that the essential germline role of His2Av is transcriptional (H2A.Z-like). Together, our findings reveal that His2Av primes germline chromatin for piRNA pathway initiation while limiting transcription-replication conflicts during early oogenesis.

developmental biology↗

bioRxiv2025

A recurrent pathogenic BRCA2 truncating variant reveals a role for BRCA2-PCAF complex in modulating NF-κB-driven transcription

Germline monoallelic truncating mutations in BRCA2, a critical mediator of homologous recombination (HR), predispose individuals to breast and ovarian cancer. While tumorigenesis is usually attributed to biallelic inactivation, emerging evidence suggests that haploinsufficiency may suffice in certain contexts. To investigate this, we recreated two BRCA2 pathogenic truncating variants in heterozygosis in non-tumorigenic breast epithelial cells. Cells carrying a truncating mutation that was not produced prompted sensitivity to PARP inhibitors (PARPi) and reduced the HR capacity indicating haploinsufficiency. Surprisingly, the other variant was expressed as a truncated product and prompted a transcriptional rewiring. Mechanistically, the truncated BRCA2 product formed abnormal oligomers with full-length BRCA2 and bound to the PCAF acetyltransferase, sequestering it. This led to reduced global histone H4 acetylation and decreased NF-{kappa}B transcriptional activity, ultimately impairing epithelial cell migration--a process also altered in tumors. Our findings uncover a previously unrecognized BRCA2-PCAF axis that modulates NF-{kappa}B-driven transcriptional program, a process that is co-opted by a recurrent BRCA2 pathogenic variant.

cancer biology↗

bioRxiv2018

Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1

The BRCA2 tumor suppressor protein is involved in the maintenance of genome integrity through its role in homologous recombination. In mitosis, BRCA2 is phosphorylated by Polo-like kinase 1 (PLK1). Here we describe how this phosphorylation contributes to the control of mitosis. We identified two highly conserved phosphorylation sites at S193 and T207 of BRCA2. Phosphorylated-T207 is a bona fide docking site for PLK1 as illustrated by the crystal structure of the BRCA2 peptide bound to PLK1 Polo-box domain. We found that BRCA2 bound to PLK1 forms a complex with the phosphatase PP2A and phosphorylated-BUBR1. Reducing BRCA2 binding to PLK1, as observed in BRCA2 breast cancer variants S206C and T207A, alters the tetrameric complex resulting in misaligned chromosomes, faulty chromosome segregation and aneuploidy. We thus reveal a direct role of BRCA2 in the alignment of chromosomes, distinct from its DNA repair function, with important consequences on chromosome stability. These findings may explain in part the aneuploidy observed in BRCA2-mutated tumors.

cell biology↗