ANAPC13

ANAPC13 (Swm1/Apc13) is a small, evolutionarily conserved core subunit of the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that drives cell cycle transitions (PMID:15060174, PMID:12609981). Within the complex it promotes the stable association of the essential TPR subunits CDC16/Cdc16 and CDC27/Cdc23 with the APC/C, and structural mapping places APC13 in the 'Arc Lamp' sub-complex alongside APC16 and CDC26, in proximity to the homodimerizing TPR subunits APC3, APC6, APC7, and APC8 (PMID:15060174, PMID:25490258). Loss of the subunit reduces APC/C ubiquitin ligase activity in vitro and delays APC/C-dependent cell cycle events in vivo, with deletion causing G2/M accumulation (PMID:15060174, PMID:12609981). Biallelic loss-of-function mutations in ANAPC13 cause human and mouse oocyte maturation arrest at metaphase I by disrupting APC/C subunit composition and impairing the ubiquitin ligase activity required for the metaphase I-to-anaphase I transition, without altering spindle assembly checkpoint dynamics; wild-type mRNA partially rescues polar body extrusion (PMID:41997520). In budding yeast the orthologue is additionally required for late sporulation and cell wall integrity, functions mechanistically tied to its APC/C role (PMID:10022899, PMID:15135545).

1. 1999 Medium

   Before its assignment to the APC/C, the yeast orthologue was first defined functionally as a nuclear factor needed for completion of late sporulation, establishing a developmental cell-cycle-linked role distinct from a known MAP kinase pathway.

   Evidence Gene deletion, sporulation and epistasis assays, transcriptional reporters and nuclear localization in S. cerevisiae

   PMID:10022899

   Open questions at the time

   • Molecular identity of the pathway and biochemical activity unknown at this stage
   • No link yet to APC/C
   • Mechanism of sporulation gene control not resolved
2. 2003 High

   The question of whether Swm1 was a bona fide APC/C component was answered by identifying it as a constitutive core subunit present across the cell cycle and in meiosis that interacts with Cdc23/APC8 and Apc5.

   Evidence Mass spectrometry of purified APC, co-purification with tagged subunits, in vitro transcription/translation interaction, FACS cell cycle analysis in budding yeast

   PMID:12609981

   Open questions at the time

   • Did not establish the functional consequence for ligase activity
   • Specific structural contacts unresolved
3. 2004 High

   The mechanistic role within the complex was defined: the subunit stabilizes the TPR subunits Cdc16 and Cdc27, and its loss reduces ligase activity and delays cell cycle progression, with conservation demonstrated by cross-species complementation.

   Evidence Mass spectrometry, co-purification, in vitro ubiquitin ligase reconstitution, complementation across human and fission yeast homologues, cell cycle analysis

   PMID:15060174

   Open questions at the time

   • Atomic-resolution placement of the subunit not yet determined
   • Direct contacts with TPR subunits inferred from association assays
4. 2004 Medium

   A parallel yeast study connected the subunit to cell wall integrity, showing reduced glucan synthase activity and delocalized chitin overdeposition, extending the phenotypic consequences of its loss.

   Evidence Growth assays at restrictive temperature, electron microscopy, glucan synthase and chitin quantification, swm1 chs3 double-mutant analysis

   PMID:15135545

   Open questions at the time

   • Causal chain from APC/C function to cell wall phenotype not directly demonstrated
   • Single lab
5. 2014 Medium

   Structural work positioned the subunit within the APC/C architecture, placing APC13 in the 'Arc Lamp' sub-complex with APC16 and CDC26 near the stacked TPR subunits.

   Evidence X-ray crystallography of human APC3 and APC3–APC16 complex, biochemical subunit-interaction mapping, ubiquitination assays

   PMID:25490258

   Open questions at the time

   • APC13's own contacts inferred from prior data rather than directly resolved in these structures
   • No full-complex density for APC13
6. 2024 Medium

   A disease-context role emerged: the SF3B1-K700E splicing mutation aberrantly splices ANAPC13 to reduce its protein level, impairing regulatory T cell differentiation and function, linking subunit dosage to immune phenotypes.

   Evidence Treg-specific Sf3b1-K700E knock-in mouse, RNA splicing analysis, adoptive-transfer colitis assay, forced re-expression rescue

   PMID:39303038

   Open questions at the time

   • Mechanism connecting reduced ANAPC13 to Treg biology via APC/C not dissected
   • Single lab
7. 2025 High

   The clinical and mechanistic basis of a human Mendelian phenotype was established: biallelic ANAPC13 mutations cause oocyte metaphase I arrest by disrupting APC/C composition and ligase function during the metaphase I-to-anaphase I transition.

   Evidence Whole-exome sequencing, Anapc13 knock-in mouse, in vitro oocyte maturation, proteomics, molecular interaction assays, mRNA rescue microinjection

   PMID:41997520

   Open questions at the time

   • Only partial rescue achieved (49%)
   • Precise structural disruption of subunit contacts not resolved
   • Spindle checkpoint shown unaffected but downstream substrate stabilization not catalogued
8. 2025 Low

   An additional infertility case associated mutations with aberrant cellular localization of the protein and predicted disrupted inter-subunit bonds, adding candidate variants to the maturation-arrest spectrum.

   Evidence Whole-exome sequencing, in vitro localization assay, computational structural modelling in a single infertile female

   PMID:40238067

   Open questions at the time

   • Single case with no functional rescue
   • Localization from in vitro overexpression only
   • Structural prediction is computational, not experimentally resolved

• How ANAPC13 dosage and subunit-assembly defects translate into tissue-specific outcomes (oocyte arrest versus Treg dysfunction) and which APC/C substrates are differentially affected remains unresolved.
• No substrate-level map of APC/C dysregulation across tissues
• No high-resolution structure of human APC13 within the assembled complex
• Tissue-specificity of phenotypes unexplained