CDCA5

CDCA5 (sororin) is a regulator of sister chromatid cohesion that is essential for orderly cell cycle progression: its depletion causes G2/M arrest, severe sister chromatid aggregation defects, and apoptosis (PMID:34509929). Its abundance is controlled at multiple levels — transcriptionally it is a direct target of E2F1 (PMID:31205541), while at the protein level it is stabilized by TPI1 (PMID:35509067) and targeted for polyubiquitin-dependent proteasomal degradation by the E3 ubiquitin ligase adaptor SPOP through a degron-dependent mechanism that is impaired by cancer-associated SPOP mutations (PMID:34509929). Its production is further gated post-transcriptionally by the spliceosome component CDC40, whose loss causes retention of the first CDCA5 intron and reduced CDCA5 protein (PMID:39747150). Beyond cohesion, CDCA5 physically engages EEF1A1 (PMID:38658931), and acts to promote E2F1 occupancy of the FOXM1 promoter, driving FOXM1 upregulation and Wnt/β-catenin activation (PMID:38978058). Across cancer contexts these activities converge on sustained proliferation and invasion, with PI3K/AKT/mTOR signaling placed mechanistically downstream of CDCA5 (PMID:35509067, PMID:41026320).

1. 2019 Medium

   Established how CDCA5 expression is driven in proliferating cancer cells by identifying its upstream transcriptional activator, linking it to the E2F cell-cycle program.

   Evidence Luciferase reporter assay and ChIP in hepatocellular carcinoma cells

   PMID:31205541

   Open questions at the time

   • Does not address whether E2F1 regulation holds across other tissues
   • No measurement of how this transcriptional input couples to cohesion function
2. 2020 Low

   Connected CDCA5 to cell cycle effectors and survival, showing depletion lowers CDC2/Cyclin B1 and PI3K/AKT/mTOR output while engaging the mitochondrial apoptotic pathway.

   Evidence shRNA knockdown/overexpression with western blot and flow cytometry in bladder cancer cells

   PMID:32201512

   Open questions at the time

   • Western-blot pathway readouts without direct interaction or epistasis
   • Does not establish whether PI3K/AKT/mTOR effects are direct or secondary to cell-cycle arrest
3. 2021 Medium

   Resolved how CDCA5 protein levels are degraded by identifying SPOP as the E3 adaptor mediating degron-dependent polyubiquitination, and explained how SPOP mutations elevate CDCA5.

   Evidence Reciprocal Co-IP, ubiquitination assay, and degron-dependency rescue in prostate cancer cells

   PMID:34509929

   Open questions at the time

   • Specific lysine residues ubiquitinated not mapped
   • Whether degradation is cell-cycle phase-restricted not addressed
4. 2021 Medium

   Confirmed the cohesion-maintenance function of CDCA5 by defining the cellular consequences of its loss, anchoring its sororin identity.

   Evidence shRNA knockdown with flow cytometry and microscopy of sister chromatid phenotypes in prostate cancer cells

   PMID:34509929

   Open questions at the time

   • Molecular partners at the cohesin complex not characterized in this corpus
   • Does not distinguish direct cohesion role from indirect cell-cycle arrest
5. 2021 Low

   Placed CDCA5 upstream of ERK signaling, extending its proliferative role beyond the cell-cycle machinery.

   Evidence shRNA knockdown with phospho-ERK western blot, proliferation and xenograft assays in prostate cancer

   PMID:33650660

   Open questions at the time

   • Single phosphorylation readout for pathway placement
   • Corrigendum issued for figure assembly error
   • Mechanism linking CDCA5 to ERK undefined
6. 2022 Medium

   Identified TPI1 as a CDCA5 binding partner that stabilizes the protein, revealing a positive post-translational input that counterbalances SPOP-mediated turnover.

   Evidence Co-IP, mass spectrometry, and ubiquitination assays in breast cancer cells

   PMID:35509067

   Open questions at the time

   • Whether TPI1 directly competes with SPOP not tested
   • Structural basis of the TPI1–CDCA5 interaction unknown
7. 2022 Low

   Positioned PDS5A downstream of CDCA5 through epistasis, linking CDCA5 to a cohesion-associated effector in proliferation and migration.

   Evidence shRNA knockdown with PDS5A overexpression rescue, western blot and functional assays in breast cancer

   PMID:35506437

   Open questions at the time

   • No direct binding assay between CDCA5 and PDS5A
   • Single-lab epistasis only
8. 2023 Low

   Added KLF5 as a second transcriptional activator of CDCA5, indicating context-dependent upstream control in ovarian cancer.

   Evidence ChIP, promoter binding assay, and KLF5 overexpression rescue in epithelial ovarian cancer cells

   PMID:37247719

   Open questions at the time

   • Orthogonal promoter validation not detailed
   • Relationship to E2F1-driven regulation not reconciled
9. 2024 Medium

   Defined a transcriptional output of CDCA5 by showing it promotes E2F1 binding to the FOXM1 promoter, driving FOXM1 and Wnt/β-catenin activation.

   Evidence Co-IP, ChIP, dual-luciferase reporter, and FOXM1 knockdown rescue in breast cancer cells

   PMID:38978058

   Open questions at the time

   • How a cohesion protein facilitates E2F1 promoter occupancy mechanistically unclear
   • Direct CDCA5–E2F1 contact at chromatin not structurally defined
10. 2024 Medium

    Identified EEF1A1 as a direct CDCA5 partner coupling the protein to mTOR signaling in renal cancer, broadening its interactome beyond the cohesion apparatus.

    Evidence Co-IP and LC-MS/MS with knockdown/overexpression in clear cell renal cell carcinoma

    PMID:38658931

    Open questions at the time

    • Interaction interface not mapped
    • Whether EEF1A1 binding is cohesion-independent unknown
11. 2024 Low

    Linked CDCA5 to invasion via TGF-β1/Smad2/3 signaling, extending its role into metastatic phenotypes.

    Evidence RNA sequencing, invasion/migration assays, and pathway inhibitor experiments in ovarian cancer

    PMID:38539247

    Open questions at the time

    • No direct protein interaction shown
    • Pathway placement inferred from transcriptomics
12. 2025 Medium

    Revealed post-transcriptional control of CDCA5 by the spliceosome, showing CDC40 loss causes first-intron retention and reduced CDCA5 protein.

    Evidence siRNA knockdown, splicing analysis, RT-PCR for intron retention, and protein-protein interaction assays

    PMID:39747150

    Open questions at the time

    • Whether CDC40 directly binds CDCA5 pre-mRNA not shown
    • Physiological conditions altering this splicing not defined
13. 2025 Low

    Identified Cyclin A2 as a CDCA5 partner in lung cancer and connected both to berberine sensitivity, reinforcing CDCA5's cell-cycle interactions.

    Evidence Co-IP, western blot, and overexpression rescue in NSCLC cells

    PMID:40155519

    Open questions at the time

    • Single Co-IP without reciprocal validation
    • Functional context limited to drug treatment
14. 2025 Low

    Demonstrated therapeutic synergy of CDCA5 depletion with olaparib via PI3K/AKT/mTOR suppression, autophagy, and DNA damage, placing the pathway downstream of CDCA5.

    Evidence siRNA knockdown, CCK-8, immunofluorescence, TEM, PI3K pathway activator rescue, and xenograft in BRCA1-mutated ovarian cancer

    PMID:41026320

    Open questions at the time

    • No direct interaction data
    • Mechanism linking CDCA5 to DNA damage repair undefined

• How CDCA5's core cohesion function mechanistically connects to the multiple oncogenic signaling cascades (PI3K/AKT/mTOR, ERK, TGF-β1/Smad, Wnt) attributed to it remains unresolved.
• No structural model of CDCA5 in any complex within this corpus
• Whether signaling roles are direct or downstream of cell-cycle arrest unresolved
• Direct cohesin-complex partners not characterized in the corpus