SUGP1

SUGP1 is a spliceosomal G-patch protein that ensures accurate branchsite recognition and 3' splice site selection by physically linking the U2 snRNP component SF3B1 to the catalytic RNA helicase machinery (PMID:31474574, PMID:36459648). It directly binds SF3B1 through regions flanking its G-patch motif, and cancer-associated SF3B1 hotspot mutations (e.g., K700E) act by reducing SUGP1 association with the spliceosome; SUGP1 knockdown alone fully phenocopies the aberrant cryptic 3' splice site usage of mutant SF3B1, and SUGP1 overexpression partially rescues it, identifying loss of the SF3B1–SUGP1 interaction as the molecular defect underlying mutant SF3B1 missplicing (PMID:31474574, PMID:37977822). SUGP1 uses its G-patch motif to directly bind and activate the DEAH-box helicase DHX15, an interaction defined at atomic resolution; within the trimeric SF3B1–SUGP1–DHX15 assembly the SF3B1 contact 'loops out' the G-patch for DHX15 engagement, and this helicase recruitment underlies a splicing quality-control function that represses suboptimal introns with weak splice sites and cryptic branch points, dependent on DHX15 ATPase activity and the SUGP1 ULM domain (PMID:36459648, PMID:37977822, PMID:37805921). Independently of its core spliceosomal role, SUGP1 controls cholesterol homeostasis by regulating HMGCR alternative splicing and transcript stability in hepatocytes, with hepatic overexpression raising plasma cholesterol and knockdown reducing cholesterol synthesis (PMID:27206982). Recurrent somatic SUGP1 mutations and loss-of-heterozygosity across cancers genetically place SUGP1 in the same splicing pathway as SF3B1, reproducing the mutant-SF3B1 missplicing signature (PMID:32332164, PMID:33057152).

1. 2003 Low

   Established SUGP1's domain architecture, framing it as a candidate splicing factor before any functional test.

   Evidence Bioinformatic domain analysis and cDNA cloning identifying two SURP motifs and a C-terminal G-patch domain

   PMID:12594045

   Open questions at the time

   • No functional experiment performed on SUGP1 itself
   • Domain assignments inferred from homology only
   • No interaction partners identified
2. 2016 Medium

   Connected SUGP1 to a physiological output—cholesterol metabolism—by showing it regulates HMGCR alternative splicing and transcript stability.

   Evidence Mouse hepatic overexpression with plasma cholesterol measurement, hepatoma cell knockdown, RT-PCR for HMGCR splicing, mRNA stability and LDL uptake assays

   PMID:27206982

   Open questions at the time

   • Mechanism linking SUGP1 to HMGCR splice site choice not defined
   • Single lab
   • Relationship to SUGP1's core spliceosomal role unclear
3. 2019 High

   Identified loss of SF3B1–SUGP1 interaction as the causal molecular defect of mutant SF3B1, resolving how a single SF3B1 hotspot mutation produces widespread missplicing.

   Evidence Affinity purification/MS of WT vs K700E SF3B1 complexes, siRNA knockdown with RNA-seq phenocopy, and overexpression rescue in patient-derived cells

   PMID:31474574

   Open questions at the time

   • Structural basis of SF3B1–SUGP1 contact not yet defined
   • Downstream effector of SUGP1 not identified
   • Why specific 3' splice sites are sensitive unresolved
4. 2020 Medium

   Placed SUGP1 genetically within the SF3B1 splicing pathway in cancer by showing SUGP1 somatic mutations and LOH reproduce the mutant-SF3B1 missplicing signature.

   Evidence Pan-cancer RNA-seq screens (TCGA) with experimental validation of multiple SUGP1 mutants and loss-of-function models in cell lines

   PMID:32332164 PMID:33057152

   Open questions at the time

   • Mechanism by which each mutation impairs function not dissected at residue level
   • Oncogenic consequence of the missplicing not established
   • Single-lab validation per study
5. 2022 High

   Identified DHX15 as the cognate helicase activated by SUGP1's G-patch, providing the catalytic effector downstream of SF3B1–SUGP1.

   Evidence Co-IP/pulldown, knockdown with RNA-seq, DHX15 mutant and SUGP1-G-patch fusion rescue, and crystal structure of the DHX15–SUGP1 G-patch complex

   PMID:36459648

   Open questions at the time

   • Structure limited to the G-patch–DHX15 interface, not the full trimer
   • RNA substrate engaged by the helicase not defined
   • How helicase action enforces correct splice site choice unresolved
6. 2023 High

   Defined the trimeric SF3B1–SUGP1–DHX15 architecture and showed all interface cancer mutations weaken SF3B1–SUGP1 binding, and that DHX15 quality control requires SUGP1's G-patch and ULM domains.

   Evidence Structural modeling with interface mutagenesis, co-IP and splicing reporter assays; auxin-inducible degron depletion with nascent/mature RNA-seq and domain mutagenesis

   PMID:37805921 PMID:37977822

   Open questions at the time

   • No experimental structure of the full trimeric complex
   • ULM-binding partner in this context not directly mapped
   • How the 'looped-out' G-patch is regulated dynamically unknown
7. 2025 Medium

   Demonstrated SUGP1's uniqueness among splicing factors—only SUGP1 loss recapitulates nearly all mutant-SF3B1 defects—and resolved that AQR acts only indirectly via SUGP1.

   Evidence Computational screen of 600 splicing factors with knockdown/knockout RNA-seq; Western blot for SUGP1 protein after AQR knockdown; preprint follow-up on AQR-SUGP1 dependency

   PMID:40027711 PMID:40714635

   Open questions at the time

   • AQR-SUGP1 link partly from a preprint
   • How AQR loss causes SUGP1 missplicing not mechanistically detailed
   • Full set of SUGP1-dependent vs SUGP1-independent SF3B1 effects not partitioned

• How disruption of the SF3B1–SUGP1–DHX15 axis is converted into oncogenic phenotypes, and how branch-site selection is mechanistically governed by SUGP1, remain open.
• No full-length trimeric complex structure
• Causal link between specific missplicing events and tumorigenesis unestablished
• Branch-site profiling consequences (U2 IP-seq) reported only in preprint