Journal Article

An anciently diverged family of RNA binding proteins maintain correct splicing of a class of ultra-long exons through cryptic splice site repression

Wilson, Stuart A, Cheung, Kathleen, Gazzara, Matthew R, Dalgliesh, Caroline, Siachisumo, Chileleko, Smith, Graham R, Aldalaqan, Saad, Cockell, Simon J, Kheirollahi Chadegani, Mahsa, Munkley, Jennifer, Yonchev, Ivaylo D, James, Katherine, Barash, Yoseph, Elliott, David J, Luzzi, Sara, Ehrmann, Ingrid E, Hysenaj, Gerald

2024

Overview

Previously, we showed that the germ cell-specific nuclear protein RBMXL2 represses cryptic splicing patterns during meiosis and is required for male fertility (Ehrmann et al., 2019). Here, we show that in somatic cells the similar yet ubiquitously expressed RBMX protein has similar functions. RBMX regulates a distinct class of exons that exceed the median human exon size. RBMX protein-RNA interactions are enriched within ultra-long exons, particularly within genes involved in genome stability, and repress the selection of cryptic splice sites that would compromise gene function. The RBMX gene is silenced during male meiosis due to sex chromosome inactivation. To test whether RBMXL2 might replace the function of RBMX during meiosis we induced expression of RBMXL2 and the more distantly related RBMY protein in somatic cells, finding each could rescue aberrant patterns of RNA processing caused by RBMX depletion. The C-terminal disordered domain of RBMXL2 is sufficient to rescue proper splicing control after RBMX depletion. Our data indicate that RBMX and RBMXL2 have parallel roles in somatic tissues and the germline that must have been conserved for at least 200 million years of mammalian evolution. We propose RBMX family proteins are particularly important for the splicing inclusion of some ultra-long exons with increased intrinsic susceptibility to cryptic splice site selection.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Binding sites / Cell division / Cell size / Chromosomes and Gene Expression / exon / Exons / Exons - genetics / Gene expression / Gene silencing / Genomes / Heterogeneous-Nuclear Ribonucleoproteins / Humans / Male / Meiosis / Meiosis - genetics / Proteins / Research Advance / RNA / RNA polymerase / RNA processing / RNA Splice Sites - genetics / RNA Splicing / RNA-binding protein / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Sex chromosomes / Somatic cells / Splicing / X chromosomes / Y chromosomes