Biology subjects

Vaysse-Zinkhofer, W.

Publications and source records attributed to Vaysse-Zinkhofer, W..

3 recordsLinked to original sources

bioRxiv2025

Cul5Wsb2 uses BCL2 proteins as co-receptors to target Bim for degradation.

Anti-apoptotic BCL2 family proteins (e.g. BCL-XL) protect cells by binding and inhibiting pro-apoptotic proteins (e.g. BIM). Although CUL5WSB2 was linked to apoptosis regulation, its substrate and mechanism were unknown. We find that BCL2 proteins recruit BIM to CUL5WSB2 for degradation. WSB2 recognizes BCL-XL through a motif conserved between BCL-XL, BCL-W and BCL2, but not MCL1. Disruption of this interaction through mutation of either BCL-XL or WSB2 blocks the binding of WSB2 to the BCL-XL/BIM dimer. WSB2 also associates with the MCL1/BIM dimer through a separate WSB2 interface, suggesting that WSB2 has evolved independent two means to target BIM. While WSB2 is not essential in most cells, it is essential in cells derived from tumors of the nervous system, and knockdown of WSB2 in these lines causes death and apoptosis. This work uncovers a novel mechanism of apoptosis regulation, with implications for developing therapies against neuroblastomas and other cancers reliant on this pathway for survival.

biochemistry↗

bioRxiv2023

Mutant mice lacking alternatively spliced p53 isoforms unveil Ackr4 as a male-specific prognostic factor in Myc-driven B-cell lymphomas

The Trp53 gene encodes several isoforms of elusive biological significance. Here we show that mice lacking the Trp53 Alternatively Spliced (AS) exon, thereby expressing the canonical p53 protein but not isoforms with the AS C-terminus, have unexpectedly lost a male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in p53+/+ E-Myc males compared to p53{Delta}AS/{Delta}AS E-Myc males, but also compared to p53+/+ E-Myc and p53{Delta}AS/{Delta}AS E-Myc females. Pre-tumoral splenic cells from p53+/+ E-Myc males exhibited a higher expression of Ackr4, encoding an atypical chemokine receptor with tumor suppressive effects. We identified Ackr4 as a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine E-Myc-induced and human Burkitt lymphomas. Furthermore, the knockout of ACKR4 increased the chemokine-guided migration of Burkitt lymphoma cells. These data demonstrate the functional relevance of alternatively spliced p53 isoforms and reveal sex disparities in Myc-driven lymphomagenesis.

cancer biology↗

bioRxiv2019

Resection and repair of a Cas9 double-strand break at CTG trinucleotide repeats induces local and extensive chromosomal rearrangements

Microsatellites are short tandem repeats, ubiquitous in all eukaryotes and represent [~]2% of the human genome. Among them, trinucleotide repeats are responsible for more than two dozen neurological and developmental disorders. Targeting microsatellites with dedicated DNA endonucleases could become a viable option for patients affected with dramatic neurodegenerative disorders. Here, we used the Streptococcus pyogenes Cas9 to induce a double-strand break within the expanded CTG repeat involved in myotonic dystrophy type 1, integrated in a yeast chromosome. Repair of this double-strand break generated unexpected large chromosomal rearrangements around the repeat tract. These rearrangements depended on RAD52, DNL4 and SAE2, and both non-homologous end-joining and single-strand annealing pathways were involved. Resection and repair of the double-strand break (DSB) were totally abolished in a rad50{Delta} strain, whereas they were impaired in a sae2{Delta} mutant, only on the DSB end containing most of the repeat tract. This proved that Sae2 plays significant different roles in resecting a DSB end containing a repeated and structured sequence as compared to a non-repeated DSB end.\n\nIn addition, we also discovered that gene conversion was less efficient when the DSB could be repaired using a homologous template, suggesting that the trinucleotide repeat may interfer with gene conversion too. Altogether, these data show that SpCas9 is probably not a good choice when inducing a double-strand break at or near a microsatellite, especially in mammalian genomes that contain many more dispersed repeated elements than the yeast genome.

genetics↗