BUD13

BUD13 is a core component of the retention and splicing (RES) complex that functions as an RNA-binding protein to promote efficient pre-mRNA splicing and counteract intron retention genome-wide. CLIP-based studies demonstrate that BUD13 binds directly to a subset of introns with shared sequence characteristics, and its loss leads to elevated intron retention, reduced spliceosomal protein levels, nuclear morphology defects, and impaired production of mature transcripts such as Irf7, thereby dampening the type I interferon response (PMID:30639243, PMID:35670808). Beyond splicing, BUD13 acts as an endogenous inhibitor of the Fbw7 E3 ubiquitin ligase by interfering with Fbw7–Cul1 complex assembly; cancer-associated BUD13 mutations that evade RSK3-mediated phosphorylation enhance Fbw7 substrate stability and promote colon cancer growth (PMID:37382881). Homozygous loss-of-function variants in BUD13 cause a Mendelian disorder characterized by global intron retention and nuclear envelope abnormalities, and rare variants co-segregate with specific language impairment in family studies (PMID:35670808, PMID:35053791).

1. 2019 High

   The mechanistic question of how specific introns are protected from retention was answered by showing BUD13 directly binds a defined intron subset (via CLIP) and that its loss at the Irf7 locus impairs mature mRNA production and type I interferon signaling, establishing BUD13 as a selective splicing-promoting RNA-binding protein.

   Evidence CLIP, BUD13 knockdown with global IR analysis, and VSV infection assay in macrophages

   PMID:30639243

   Open questions at the time

   • Structural basis for BUD13 recognition of its target intron features not determined
   • Whether BUD13 splicing targets beyond Irf7 have comparable functional consequences remains unexplored
   • Relationship between BUD13 and other RES complex subunits in target selection not dissected
2. 2020 Low

   BUD13 was shown to stabilize specific mRNAs when recruited by non-coding RNAs (lncRNA DBH-AS1 stabilizing FN1 mRNA), extending its function beyond splicing to post-transcriptional mRNA stabilization in cancer contexts.

   Evidence RIP, knockdown/overexpression rescue, and mRNA stability assays in diffuse large B-cell lymphoma cells

   PMID:32091157

   Open questions at the time

   • Direct binding between BUD13 and FN1 mRNA not demonstrated with purified components
   • Whether mRNA stabilization is independent of BUD13's splicing function not addressed
   • Single-laboratory finding without independent replication
3. 2021 Medium

   Genetic evidence linked BUD13 to neural development and language function, answering whether its splicing role has neurodevelopmental consequences: rare BUD13 variants co-segregated with specific language impairment in a family, and animal models confirmed neural phenotypes upon loss of function.

   Evidence Whole-exome sequencing with co-segregation analysis in an SLI family, plus animal model loss-of-function studies

   PMID:35053791

   Open questions at the time

   • Specific splicing targets disrupted in neural tissue not identified
   • Mechanistic pathway from BUD13 loss to language impairment not delineated
   • Small family study; broader cohort replication needed
4. 2022 High

   Human genetic evidence established that BUD13 is essential for genome-wide splicing fidelity and nuclear architecture: a homozygous nonsense variant caused global intron retention, reduced spliceosomal protein levels, and nuclear envelope invaginations — all rescued by BUD13 re-expression — confirming its non-redundant role in the RES complex.

   Evidence Patient exome sequencing, RNA-seq, proteomics, electron microscopy, and overexpression rescue in patient-derived dermal fibroblasts

   PMID:35670808

   Open questions at the time

   • Whether nuclear morphology defects are a direct consequence of splicing failure or reflect an independent BUD13 function is unresolved
   • Which spliceosomal proteins are downregulated due to intron retention versus other mechanisms not distinguished
   • Genotype-phenotype correlation across additional patients not available
5. 2022 Medium

   METTL3-mediated m6A modification was shown to regulate BUD13 expression itself by stabilizing BUD13 mRNA, and BUD13 in turn stabilized CDK12 mRNA to drive vasculogenic mimicry in glioblastoma, placing BUD13 within an epitranscriptomic regulatory circuit.

   Evidence m6A methylation and mRNA stability assays, knockdown, and in vivo xenograft in glioblastoma models

   PMID:36463205

   Open questions at the time

   • Direct binding of BUD13 to CDK12 mRNA not reconstituted in vitro
   • Whether m6A regulation of BUD13 occurs in non-cancer contexts is unknown
   • Contribution of BUD13's splicing versus mRNA stabilization function not separated
6. 2023 Medium

   BUD13 was found to have a splicing-independent oncogenic function as an endogenous Fbw7 inhibitor: it disrupts Fbw7–Cul1 complex formation, and cancer-associated mutations (R156C, R230Q) that evade RSK3 phosphorylation amplify this inhibitory activity, stabilizing Fbw7 substrates and promoting colon cancer.

   Evidence Co-immunoprecipitation of Fbw7–Cul1 complex, in vitro phosphorylation assays, cancer-associated mutagenesis, and tumor growth assays

   PMID:37382881

   Open questions at the time

   • Structural basis for BUD13–Fbw7 interaction not resolved
   • Whether wild-type BUD13 inhibition of Fbw7 is physiologically relevant in non-cancer settings remains unclear
   • Independent validation of BUD13 as an Fbw7 inhibitor by another group not yet available

• It remains unknown how BUD13's dual roles — as a splicing factor within the RES complex and as an Fbw7 inhibitor — are coordinated, what determines its allocation between these functions, and which BUD13 domains mediate each activity independently.
• No structural model of BUD13 in complex with RES subunits or Fbw7
• Domain-specific separation of splicing versus Fbw7-inhibitory functions not performed
• Full spectrum of BUD13-dependent splicing targets across tissues not mapped