Biology subjects

Seraphin, B.

Publications and source records attributed to Seraphin, B..

3 recordsLinked to original sources

bioRxiv2023

Multiple Myeloma associated DIS3 mutations drive AID-dependent IgH Translocations

Role of dominant DIS3 mutations in multiple myeloma (MM) remains elusive. These mutations decrease the exoribonucleolytic activity of DIS3, a key nuclear RNA-degrading enzyme. Utilizing knock-in mice with clinical Dis3 G766R variant, we demonstrate an increased frequency of aberrant chromosomal translocations in B-cells, leading to plasmacytoma, an early-stage MM model. DIS3-dependent translocations display characteristics of aberrant activation-induced deaminase (AID) activity. In clinical MM samples with DIS3 mutations, driver genes also show AID-dependent lesions. Mechanistically, mutated DIS3 accumulates on chromatin-associated RNA substrates, including aberrant AID action sites, fostering oncogenic chromosomal rearrangements. Translocations occur during immunoglobulin class switch recombination, a process otherwise unaffected in MM patients or mice with mutated DIS3. Dis3 G766R mutation does not alter chromatin architecture in activated B-cells but hijacks it to bring together enhancers with proto-oncogenes permanently. In conclusion, gain-of-function DIS3 mutations increase nuclear exosome and AID affinity to chromatin, facilitating IGH translocations and driving MM transformation.

molecular biology↗

bioRxiv2023

HELZ2: a new, interferon-regulated, human 3'-5' exoribonuclease of the RNB family is expressed from a non-canonical initiation codon

Proteins containing a RNB domain, originally identified in E. coli RNase II, are widely present throughout the tree of life. Many RNB proteins are endowed with 3-5 exoribonucleolytic activity but some have lost catalytic function during evolution. Database searches identified a new RNB domain containing protein in human: HELZ2. Analysis of genomic and expression data with evolutionary information suggested that the human HELZ2 protein is produced from an unforeseen non-canonical initiation codon in Hominidae. This unusual property was confirmed experimentally, extending the human protein by 247 residues. Human HELZ2 was further shown to be an active ribonuclease despite the substitution of a key residue in its catalytic center. HELZ2 harbors also two RNA helicase domains and several zinc-fingers and its expression is induced by interferon treatment. We demonstrate that HELZ2 is able to degrade structured RNAs through the coordinated ATP-dependent displacement of duplex RNA mediated by its RNA helicase domains and its 3-5 ribonucleolytic action. The expression characteristics and biochemical properties of HELZ2 support a role for this factor in response to viruses and/or mobile elements.

molecular biology↗

bioRxiv2022

The S. cerevisiae m6A-reader Pho92 impacts meiotic recombination by controlling key methylated transcripts

N6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNAs, participates in the post-transcriptional control of gene expression. In Saccharomyces cerevisiae, m6A is only found during meiosis. Although the deletion of the m6A- methyltransferase Ime4 impairs this process, the molecular impact of m6A on gene expression remains ill defined. Here we investigated the function of the budding yeast m6A reader Pho92. We found that Pho92 is specifically expressed during meiosis and impacts meiotic progression. We used high-throughput RNA sequencing and mapping of Pho92-binding sites following UV-crosslinking to show that Pho92 is recruited to specific mRNAs in an m6A-dependent manner during the meiotic prophase, preceding their down-regulation. Strikingly, point mutations altering m6A sites in mRNAs targeted by Pho92 are sufficient to delay their down-regulation and, in one case, to impact meiotic progression. Altogether, our results indicate that Pho92 facilitate the meiotic progression by accelerating the down-regulation of timely-regulated mRNAs during meiotic recombination.

molecular biology↗