RBM6

RBM6 is a nuclear RNA-binding protein that couples mRNA recognition to control of DNA double-strand break repair and chromatin-based transcriptional regulation (PMID:34718714, PMID:39344314). It contains two RNA recognition motifs that confer direct RNA-binding activity, originally shown by specific binding to poly(G) homopolymers (PMID:10353602), and genome-wide it engages a large set of mRNAs through preferential GGCGAUG and CUCU motifs, with targets enriched for proliferation- and apoptosis-associated genes whose alternative splicing depends on RBM6 (PMID:39344314). Within the nucleus RBM6 localizes to splicing speckles/interchromatin granule clusters and to nascent transcripts, with a repetitive N-terminal region that drives oligomerization and assembly of bead-like structures at the IGC periphery (PMID:21086038). RBM6 promotes homologous recombination repair through two separable activities: an alternative splicing-coupled nonstop-decay mechanism that maintains levels of the HR regulator Fe65/APBB1 (PMID:34718714), and a splicing-independent function in which its G-patch domain mediates recruitment to break sites and interaction with Rad51 to support Rad51 foci formation, with five G-patch glycine residues required for damage-site accumulation but dispensable for splicing (PMID:36941773). Consistent with this repair role, RBM6-deficient cancer cells are sensitized to ATM inhibition, PARP inhibition, and cisplatin (PMID:34718714). RBM6 additionally forms a complex with the deacetylase SIRT7 that lowers H3K18 acetylation at the OSX promoter to suppress osteogenic differentiation (PMID:33684230). A recurrent t(3;5) translocation fuses RBM6 to CSF1R, generating a constitutively active kinase fusion that drives myeloproliferative disease (PMID:17360941).

1. 1999 Medium

   Establishing that RBM6 is a bona fide RNA-binding protein answered whether its RRM domains were functional, anchoring all later RNA-dependent models.

   Evidence In vitro RNA binding assay with recombinant protein containing the RRM domains

   PMID:10353602

   Open questions at the time

   • Binding to poly(G) homopolymers in vitro does not define physiological mRNA targets
   • No cellular function assigned at this stage
   • Single method, single lab
2. 2007 High

   Identifying the RBM6-CSF1R fusion answered how a chromosomal translocation involving RBM6 contributes to leukemia, showing the fusion drives constitutive kinase signaling.

   Evidence 5'RACE fusion identification, IL-3-independent BaF3 growth assay, and murine transplant model

   PMID:17360941

   Open questions at the time

   • The oncogenic driver is CSF1R kinase activity, not native RBM6 function
   • Contribution of the RBM6 portion to fusion behavior not dissected
3. 2010 Medium

   Mapping RBM6 to splicing speckles/IGCs and defining an N-terminal oligomerization domain answered where RBM6 acts in the nucleus and how it self-assembles on RNP structures.

   Evidence Immunostaining, tagged-protein expression, Xenopus lampbrush spreads, and deletion mapping

   PMID:21086038

   Open questions at the time

   • Functional consequence of oligomerization for splicing or repair not established
   • Molecular partners at IGCs not identified
4. 2021 High

   Linking RBM6 to HR repair via splicing-coupled nonstop-decay of Fe65/APBB1 answered how an RNA-binding protein influences DNA repair and revealed a synthetic-lethal therapeutic vulnerability.

   Evidence Knockdown with splicing analysis, HR reporter assays, drug sensitivity tests, and mouse xenografts

   PMID:34718714

   Open questions at the time

   • Whether splicing regulation fully accounts for the HR phenotype was not resolved
   • Direct binding of RBM6 to the APBB1 transcript not shown in this study
5. 2021 Medium

   Defining the RBM6-SIRT7 complex answered how RBM6 contributes to chromatin regulation, showing it directs histone deacetylation to a developmental gene promoter.

   Evidence Co-immunoprecipitation, ChIP for H3K18Ac at the OSX promoter, knockdown, and in vivo osteogenesis assay

   PMID:33684230

   Open questions at the time

   • Whether RBM6 recruitment to OSX depends on its RNA-binding activity is unknown
   • Co-IP without reciprocal/structural validation of the complex interface
6. 2023 High

   Dissecting the G-patch domain answered whether RBM6 has a repair role beyond splicing, separating a splicing-independent Rad51-recruitment function from its splicing activity.

   Evidence Domain mutagenesis, live-cell DSB recruitment imaging, Rad51 Co-IP and foci quantification, and HR reporter assays

   PMID:36941773

   Open questions at the time

   • How PARP1 indirectly governs RBM6 recruitment is unresolved
   • Structural basis of the G-patch-Rad51 interaction not determined
7. 2024 Medium

   Genome-wide iRIP-seq answered which transcripts RBM6 binds directly and defined its sequence preferences, connecting binding to splicing of proliferation/apoptosis genes.

   Evidence iRIP-seq in HeLa cells with transcriptome sequencing after knockdown

   PMID:39344314

   Open questions at the time

   • Which bound transcripts are functionally regulated versus passively bound not resolved
   • Motif preference not validated by mutagenesis
8. 2025 Low

   Examining migration genes in prostate cancer addressed whether RBM6's regulatory output is fixed, showing it is context-dependent on ZEB1 levels.

   Evidence Migration assays, RNA pulldown, and RNA immunoprecipitation in prostate cancer cells

   PMID:39900560

   Open questions at the time

   • Single lab, single paper, context-specific with limited mechanistic pathway placement
   • How ZEB1 switches RBM6 target preference is unexplained
   • Direct splicing versus expression mechanism on CDH1/MMP16 not distinguished

• How RBM6's RNA-binding, oligomerization, splicing, and direct Rad51-recruitment activities are coordinated into a single regulatory program remains unresolved.
• No structural model integrating RRM, N-terminal oligomerization, and G-patch domains
• Mechanism linking PARP1 activity to RBM6 recruitment unknown
• Whether IGC localization is required for repair or splicing functions untested