CDCA5

CDCA5 (sororin) is a cell cycle-regulated cohesin accessory protein that promotes cell proliferation through sister chromatid cohesion and activation of multiple mitogenic signaling pathways. Its transcription is directly driven by E2F1 and KLF5, while its protein stability is controlled by SPOP-mediated polyubiquitination and proteasomal degradation, with TPI1 acting as a stabilizer (PMID:31205541, PMID:34509929, PMID:37247719, PMID:35509067). CDCA5 functionally interacts with PDS5A to regulate cohesion-associated processes, with EEF1A1 to activate mTOR signaling, and promotes E2F1 occupancy at the FOXM1 promoter to drive transcription through the Wnt/β-catenin axis (PMID:35506437, PMID:38658931, PMID:38978058). Proper splicing of CDCA5 pre-mRNA depends on the spliceosome component CDC40, whose depletion causes intron 1 retention and loss of CDCA5 protein (PMID:39747150).

1. 2018 Low

   Establishing that CDCA5 functions upstream of G1/S cell cycle regulators showed it is not merely a cohesion factor but an active driver of cell cycle progression beyond its canonical mitotic role.

   Evidence siRNA knockdown in gastric cancer cells with flow cytometry showing G1 arrest and Cyclin E1 downregulation

   PMID:29326043

   Open questions at the time

   • No direct binding between CDCA5 and Cyclin E1 demonstrated
   • Single cell type tested
   • Mechanism linking CDCA5 to Cyclin E1 expression unknown
2. 2019 Medium

   Identifying E2F1 as a direct transcriptional activator of CDCA5 connected its cell cycle-dependent expression to a known G1/S transcription factor and linked CDCA5 function to AKT signaling.

   Evidence ChIP and luciferase reporter assay in hepatocellular carcinoma cells plus knockdown with AKT pathway readouts

   PMID:31205541

   Open questions at the time

   • Whether E2F1 is the predominant transcriptional driver in non-cancer contexts is unknown
   • Mechanism connecting CDCA5 to AKT activation not defined
3. 2020 Low

   Demonstrating that CDCA5 upregulates CDC2/Cyclin B1 and activates PI3K/AKT/mTOR signaling broadened its downstream effector network beyond G1/S to G2/M regulators.

   Evidence siRNA knockdown and overexpression in bladder cancer cells with western blot for cell cycle proteins and PI3K/AKT/mTOR pathway components

   PMID:32201512

   Open questions at the time

   • No direct interaction between CDCA5 and CDC2 or Cyclin B1 shown
   • Mechanism of PI3K/AKT activation by CDCA5 remains indirect
   • Single cancer type
4. 2021 High

   Discovering SPOP-mediated ubiquitination and degradation of CDCA5 established the first direct post-translational regulatory mechanism for CDCA5 turnover and explained how prostate cancer SPOP mutations lead to CDCA5 accumulation.

   Evidence Reciprocal Co-IP, in vivo ubiquitination assays, degron mapping, and SPOP mutant epistasis experiments in prostate cancer cells

   PMID:34509929

   Open questions at the time

   • Whether other E3 ligases also target CDCA5 is unknown
   • Structural basis of SPOP–CDCA5 degron recognition not determined
5. 2022 Medium

   Identifying TPI1 as a CDCA5-stabilizing interactor and PDS5A as a functional mediator downstream of CDCA5 defined both an upstream stabilizer and a cohesion-linked effector axis.

   Evidence Co-IP with mass spectrometry for TPI1–CDCA5 interaction; shRNA knockdown-rescue with PDS5A overexpression in breast cancer cells

   PMID:35506437 PMID:35509067

   Open questions at the time

   • Mechanism by which TPI1 blocks CDCA5 ubiquitination is unclear
   • Whether PDS5A interaction is direct or indirect not resolved
   • Relationship between TPI1 stabilization and SPOP degradation not tested
6. 2023 Medium

   Demonstrating that KLF5 directly binds the CDCA5 promoter established a second transcriptional activator, revealing convergent regulation by both E2F1 and KLF5.

   Evidence ChIP and promoter binding assay with overexpression rescue in ovarian cancer cells

   PMID:37247719

   Open questions at the time

   • Whether E2F1 and KLF5 act cooperatively or redundantly on the CDCA5 promoter is unknown
   • Relative contribution of each factor in different tissues not addressed
7. 2024 Medium

   Showing that CDCA5 promotes E2F1 binding to the FOXM1 promoter revealed a transcriptional co-activator function and linked CDCA5 to Wnt/β-catenin signaling downstream of FOXM1.

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

   PMID:38978058

   Open questions at the time

   • How CDCA5 facilitates E2F1 chromatin occupancy mechanistically is unknown
   • Whether this co-activator role extends beyond the FOXM1 promoter is untested
8. 2024 Medium

   Identifying the CDCA5–EEF1A1 interaction and its regulation of mTOR signaling linked CDCA5 to translational control machinery.

   Evidence Co-IP with LC-MS/MS identification, knockdown/overexpression with mTOR pathway readouts in renal cell carcinoma, xenograft validation

   PMID:38658931

   Open questions at the time

   • Whether EEF1A1 interaction is direct or scaffolded is unknown
   • Mechanism by which this interaction activates mTOR not determined
9. 2025 Medium

   Demonstrating that CDC40-dependent splicing of CDCA5 intron 1 is required for CDCA5 protein production identified a post-transcriptional regulatory layer controlling CDCA5 levels.

   Evidence Global splicing analysis, RT-PCR for intron retention, CDC40 Co-IP with spliceosome components, knockdown with cell cycle readouts

   PMID:39747150

   Open questions at the time

   • Whether intron 1 retention is a regulatory mechanism exploited physiologically is unknown
   • Other splicing factors contributing to CDCA5 processing not identified

• The mechanism by which CDCA5 activates PI3K/AKT/mTOR and ERK signaling remains undefined at the biochemical level — whether CDCA5 acts as a scaffold, a direct kinase activator, or through an indirect cohesion-dependent mechanism is unknown.
• No reconstituted biochemical activity for CDCA5 in signaling pathway activation
• Structural basis of CDCA5 interactions with any partner not resolved
• Physiological role of CDCA5 in non-cancer (normal cell cycle) cohesion versus signaling functions not delineated in this literature