RBM27

RBM27 is a nuclear RNA-binding protein, defined by an RRM and an acidic-rich RS (ARRS) domain, that operates at the interface of nuclear RNA surveillance and mRNA processing (PMID:15741184). It functions as a component of the PAXT connection: under conditions favoring PAXT assembly it associates with the MTR4-ZFC3H1 core, and its loss causes accumulation of nuclear polyadenylated PAXT substrates, establishing a role in nuclear polyadenylated RNA turnover (PMID:31950173). RBM27 is recruited to transcription start sites of hundreds of genes together with ZFC3H1 and PAPγ, and this recruitment depends entirely on ZFC3H1, whose loss both displaces RBM27 from TSSs and increases PROMPT non-coding RNA abundance at those sites (PMID:37875486). In a distinct processing role, PABPN1 recruits RBM27 through its coiled-coil and RRM domains to promote splicing of last introns bearing weak 3' splice sites (PMID:37661812). The C. elegans ortholog RBM-26 directly binds the mRNA encoding the mitoribosomal assembly factor MALS-1 (MALSU1) to suppress its expression, thereby protecting neurons against mitochondrial dysfunction and axon degeneration; autism-associated missense variants reduce RBM-26 protein and reproduce these axonal defects (PMID:39480871).

1. 2005 Medium

   Before functional assignment, the domain architecture and subcellular behavior of the RBM27 ortholog were unknown; this work defined it as an RRM/RS-domain protein of a novel ARRS family with dynamic nuclear-speckle and cytoplasmic localization.

   Evidence Sequence analysis plus fluorescence/live imaging and domain-deletion mapping of the mouse Psc1 ortholog

   PMID:15741184

   Open questions at the time

   • No RNA target or biochemical activity assigned
   • Functional significance of cytospeckle trafficking unresolved
   • Human ortholog not directly tested
2. 2020 High

   It was unknown whether RBM27 participates in nuclear RNA decay; this study placed it within MTR4-ZFC3H1 (PAXT) complexes and showed its loss causes accumulation of nuclear polyadenylated PAXT substrates.

   Evidence Nuclear pA+-RNA proteome, MTR4-ZFC3H1 co-IP/MS, and knockdown with substrate-accumulation readout

   PMID:31950173

   Open questions at the time

   • Whether RBM27 contacts RNA directly within PAXT not resolved
   • Mechanism of RBM27 integration into the complex undefined
3. 2023 Medium

   How RBM27 reaches PAXT target loci and what processing role it has beyond decay were open; these studies showed ZFC3H1-dependent recruitment to TSSs controlling PROMPT levels, and a PABPN1-dependent role in splicing weak-3'-splice-site terminal introns.

   Evidence Genome-wide binding mapping with ZFC3H1 loss-of-function (PROMPT readout); TurboID interactome, PABPN1 depletion splicing assays, domain mapping, and tethering

   PMID:37661812 PMID:37875486

   Open questions at the time

   • Direct RNA-binding specificity of RBM27 not defined
   • Relationship between TSS recruitment and splicing role unintegrated
   • Structural basis of PABPN1-RBM27 coiled-coil/RRM interaction unknown
4. 2024 High

   Whether RBM27 has a direct mRNA target with physiological consequence was unknown; the C. elegans ortholog was shown to directly bind mals-1 (MALSU1) mRNA to repress it, with epistasis proving MALS-1 overexpression drives the mitochondrial and axon-degeneration defects, and autism variants reproducing the phenotype.

   Evidence Biochemical mRNA-binding screen, rbm-26 null genetics, rbm-26;mals-1 epistasis, axon imaging, and autism missense allele analysis (peer-reviewed and preprint)

   PMID:37873356 PMID:39480871

   Open questions at the time

   • Whether human RBM27 represses MALSU1 mRNA not tested
   • Connection between PAXT/splicing roles and this single-target repression unclear
   • Molecular basis of how variants lower protein level unresolved

• How RBM27's nuclear RNA-decay, terminal-intron splicing, and target-specific mRNA repression activities are mechanistically unified, and whether the conserved ortholog functions are shared in human neurons, remains unresolved.
• No integrated model linking PAXT, splicing, and direct mRNA repression
• No structural data on RBM27 complexes
• Direct RNA-binding specificity of human RBM27 undefined