ANAPC1

ANAPC1 (TSG24/APC1) encodes the largest scaffold subunit of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that drives cell-cycle progression (PMID:11179667). ANAPC1 exists both as a soluble pool associated with other APC/C components such as Cdc27 and as a centromere-bound pool, localizing specifically to active centromeres from prophase through anaphase—including neocentromeres but not the inactive centromere of dicentric chromosomes—indicating a function-linked rather than sequence-dependent centromere association (PMID:9418894, PMID:10607828, PMID:11129339). Consistent with a role in cell-cycle control, the protein is expressed throughout interphase, and its loss prolongs interphase and impairs normal cell-cycle progression (PMID:7929068, PMID:31303264). Biallelic loss-of-function mutations in ANAPC1, including a deep intronic variant activating a pseudoexon that triggers nonsense-mediated decay and reduces ANAPC1 protein, cause Rothmund-Thomson syndrome type 1 (PMID:31303264). Upstream, ANAPC1 transcription is controlled by the alternative NF-κB subunit RelB, which through ANAPC1 governs p21 and p53 stability and downstream Rb activity and EZH2 expression to restrain cellular senescence (PMID:25255445). Knockdown and knockout studies in osteosarcoma, colorectal, and hepatocellular cancer cells link ANAPC1 to proliferation, migration, and survival, but the molecular substrate spectrum and the biochemical basis of these phenotypes have not been characterized in the available corpus (PMID:37629076, PMID:40229946, PMID:40487972).

1. 1994 Medium

   Established that the ANAPC1 product is a ~200 kDa protein with cell-cycle-coupled expression and similarity to a known mitotic-entry regulator, framing it as a candidate cell-cycle control factor.

   Evidence Molecular cloning, antibody generation, and cell-cycle Western fractionation of mouse Tsg24

   PMID:7929068

   Open questions at the time

   • No biochemical activity assigned
   • Complex membership not yet established
   • Functional consequence of expression change untested
2. 1998 Medium

   Showed ANAPC1 partitions between a soluble APC/C-associated pool and a centromere-bound pool, connecting it physically to APC/C subunits and to mitotic chromosomes.

   Evidence Immunofluorescence, chromosome isolation, and co-immunoprecipitation with Cdc27 in mammalian cells

   PMID:9418894

   Open questions at the time

   • Centromeric substrate not identified
   • Recruitment mechanism to centromeres unknown
   • Single-lab observation
3. 2000 Medium

   Demonstrated that ANAPC1 centromere localization tracks centromere activity rather than DNA sequence, distinguishing functional from structural centromere targeting.

   Evidence Combined immunofluorescence/FISH on human neocentromeres and dicentric chromosomes, replicated across two labs

   PMID:10607828 PMID:11129339

   Open questions at the time

   • Determinant of active-centromere recruitment unresolved
   • Functional output of centromeric ANAPC1 not directly tested
4. 2001 Low

   Defined human APC1 as the largest APC/C subunit with stoichiometric co-expression of subunits, supporting that it functions exclusively within the complex.

   Evidence Full-length cDNA sequencing, chromosomal mapping, and expression analysis across tissues and cancer cells

   PMID:11179667

   Open questions at the time

   • No direct biochemical reconstitution of the complex
   • Inference rests on expression correlation, not assembly assay
5. 2014 Medium

   Placed ANAPC1 downstream of RelB transcriptional control, linking the alternative NF-κB pathway to p21/p53 stability, Rb activity, and senescence suppression.

   Evidence RelB siRNA knockdown, qPCR, Western blot, and ChIP in primary human fibroblasts

   PMID:25255445

   Open questions at the time

   • Whether ANAPC1 acts via ubiquitination of p21/p53 not shown directly
   • Single-lab pathway
   • Direct substrate engagement not tested
6. 2019 High

   Established ANAPC1 as a disease gene by showing biallelic loss-of-function causes Rothmund-Thomson syndrome type 1 and that protein reduction prolongs interphase, tying the human phenotype to a cell-cycle defect.

   Evidence Patient fibroblast splicing/Western analysis, cell-cycle duration measurement, and heterozygous knockout mouse

   PMID:31303264

   Open questions at the time

   • Tissue-specific basis of RTS phenotype unexplained
   • Which APC/C substrates accumulate upon ANAPC1 loss not defined
7. 2025 Low

   Extended ANAPC1 function to tumor and differentiation contexts, associating its depletion with reduced proliferation/migration, altered cell-cycle distribution, and changes in osteogenic and metabolic programs.

   Evidence siRNA/CRISPR knockdown in osteosarcoma, colorectal (HCT-116), and HCC cells with proliferation, migration, apoptosis, flow-cytometry, and enrichment readouts

   PMID:37629076 PMID:40229946 PMID:40487972

   Open questions at the time

   • Pathway assignment rests on knockdown phenotypes and enrichment rather than direct mechanism
   • RUNX2 and metabolic links not validated mechanistically
   • Single-lab studies per context

• The direct substrates ubiquitinated by ANAPC1-containing APC/C in the contexts above—and the structural basis by which ANAPC1 scaffolds substrate engagement—remain undefined in the corpus.
• No identified centromeric or senescence-pathway substrate
• No structural/reconstitution data on ANAPC1 scaffolding
• Mechanism linking ANAPC1 to RUNX2/metabolism unresolved