CACUL1 PN Consistency Notes
- Generated: 2026-06-18
- Project: PROTEOSTASIS
- Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
- UniProt: Q86Y37
- AIGR review status: COMPLETE
- Review batch: proteostasis-batch-2026-06-07
- Batch change status: added
Source Files Checked
Deep Research Files
- No
*-deep-research*.md file found in this gene directory.
AIGR Review Snapshot
- Description: CACUL1 (CDK2-associated and cullin domain-containing protein 1; also known as CAC1 / C10orf46) is a poorly characterized 369-amino-acid human protein containing a single cullin-repeat-like domain with disordered N- and C-terminal regions. Despite its name and cullin-fold homology, it is much shorter than canonical cullins (~750-900 aa) and there is no experimental evidence that it nucleates a functional cullin-RING ubiquitin ligase or carries a neddylation/RBX module. The best-supported activity, from a single study, is physical association with the cyclin-dependent kinase CDK2 and promotion of CDK2 kinase activity, consistent with a role in G1/S cell-cycle progression and proliferation; the protein is highly expressed in cancer tissues and cell lines, and its abundance varies across the cell cycle. A second study reported CACUL1 as a nuclear-receptor (estrogen receptor alpha) co-regulator that, in association with the histone demethylase LSD1/KDM1A, can repress ERalpha-dependent transcription. CACUL1 has also been recovered as a yeast two-hybrid interactor of ARMC5. Overall, CACUL1 is a lightly characterized cell-cycle-associated protein whose detailed molecular mechanism remains undefined.
- Existing/core annotation action counts: ACCEPT: 3; KEEP_AS_NON_CORE: 3; MARK_AS_OVER_ANNOTATED: 3; MODIFY: 1
PN Consistency Summary
- Consistency: CONTRADICTION flagged. Deep-research notes and the review explicitly argue CACUL1 is NOT a functional cullin-RING scaffold: it is a 369-aa protein with only a cullin-repeat-LIKE fold, far shorter than canonical cullins (~750-900 aa), lacking any RBX/neddylation module, with no evidence it nucleates a CRL. The review MARK_AS_OVER_ANNOTATED the two IEA cullin-domain-transfer terms (GO:0006511, GO:0031625) precisely on these grounds. Its best-supported function is CDK2 binding/activation (PMID:19829063) plus ERalpha co-repression (PMID:23178685). The PN node label itself hedges ("degenerate, possible CUL3 inhibitor"). The PN group mapping to GO:0160072 scaffold activity therefore directly conflicts with the review's conclusion.
- PN story / NEW pressure: Over-reaches. PN's projected GO:0160072 (verified real via OLS) asserts a ubiquitin-ligase-scaffold MF that the review rejects as a domain-homology over-annotation. There is no experimental support for scaffold/CRL activity. Do NOT add — this is an over-reach analogous to (worse than) the rejected broader-term precedents. The gene's defensible MF is GO:0019901 protein kinase binding (CDK2), already accepted as core in the review.
- Evidence alignment: PN cites 26238671 (a CUL3-related paper, basis for the "possible CUL3 inhibitor" hedge). Review's evidence (PMID:19829063 CDK2, 23178685 ERalpha, 28169274 ARMC5 Y2H) does not overlap; PN evidence is not in the review and supports a speculative CUL3-regulator role not adopted by the review.
- Verdict: Inconsistent — PN over-reaches. GO:0160072 scaffold MF should not propagate to CACUL1 (no scaffold evidence; review treats cullin-fold terms as over-annotation).
Full Consistency Review
- UniProt: Q86Y37 (CAC1, C10orf46) · batch: proteostasis-batch-2026-06-07 · review status: COMPLETE
- PN placement:
UPS|E3 ubiquitin and UBL ligases|Cullin|degenerate, possible CUL3 inhibitor ; PN-node mapping: type node degenerate, possible CUL3 inhibitor no_mapping; group node Cullin mapped → GO:0160072 ubiquitin ligase complex scaffold activity (ok_for_propagation, new_to_goa); class context_only (GO:0061630, too_broad).
- Consistency: CONTRADICTION flagged. Deep-research notes and the review explicitly argue CACUL1 is NOT a functional cullin-RING scaffold: it is a 369-aa protein with only a cullin-repeat-LIKE fold, far shorter than canonical cullins (~750-900 aa), lacking any RBX/neddylation module, with no evidence it nucleates a CRL. The review MARK_AS_OVER_ANNOTATED the two IEA cullin-domain-transfer terms (GO:0006511, GO:0031625) precisely on these grounds. Its best-supported function is CDK2 binding/activation (PMID:19829063) plus ERalpha co-repression (PMID:23178685). The PN node label itself hedges ("degenerate, possible CUL3 inhibitor"). The PN group mapping to GO:0160072 scaffold activity therefore directly conflicts with the review's conclusion.
- PN story / NEW pressure: Over-reaches. PN's projected GO:0160072 (verified real via OLS) asserts a ubiquitin-ligase-scaffold MF that the review rejects as a domain-homology over-annotation. There is no experimental support for scaffold/CRL activity. Do NOT add — this is an over-reach analogous to (worse than) the rejected broader-term precedents. The gene's defensible MF is GO:0019901 protein kinase binding (CDK2), already accepted as core in the review.
- Mapping strategy: This gene argues AGAINST propagating the Cullin-group GO:0160072 mapping to CACUL1. The type node (
degenerate, possible CUL3 inhibitor) is correctly no_mapping, but the group→GO:0160072 projection should be suppressed/excepted for CACUL1 because it is a degenerate non-scaffold member. The group mapping may be fine for bona fide cullins, but CACUL1 should be flagged as a member that does not inherit it.
- Evidence alignment: PN cites 26238671 (a CUL3-related paper, basis for the "possible CUL3 inhibitor" hedge). Review's evidence (PMID:19829063 CDK2, 23178685 ERalpha, 28169274 ARMC5 Y2H) does not overlap; PN evidence is not in the review and supports a speculative CUL3-regulator role not adopted by the review.
- Verdict: Inconsistent — PN over-reaches. GO:0160072 scaffold MF should not propagate to CACUL1 (no scaffold evidence; review treats cullin-fold terms as over-annotation).
- Recommended edits: Suppress/except the Cullin-group GO:0160072 projection for CACUL1; mark the node mapping as not-inherited for this degenerate member. [MAP]
PN Dossier Context
- review_batch: proteostasis-batch-2026-06-07
- review_yaml: genes/human/CACUL1/CACUL1-ai-review.yaml
- PN workbook rows: 1
PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cullin | degenerate, possible CUL3 inhibitor
- UniProt: Q86Y37
- In branches: UPS
- Signature domains: IPR001373
- Auxiliary domains: (none)
- PN references (titles):
- PN-node mapping records (path + ancestors):
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cullin|degenerate, possible CUL3 inhibitor
status=no_mapping scope= GO=[]
rationale: Reviewed as a contextual, regulatory, adaptor, or uncertain UPS bucket. The shared label does not by itself establish a safe gene-level GO propagation.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cullin
status=mapped scope=ok_for_propagation_to_go GO=[GO:0160072 ubiquitin ligase complex scaffold activity]
rationale: This PN group captures cullin or cullin-associated scaffold roles in ubiquitin ligase complexes. The shared GO molecular-function target is ubiquitin ligase complex scaffold activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
status=no_mapping scope= GO=[]
rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.
Projected GO annotations (1)
- GO:0160072 ubiquitin ligase complex scaffold activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cullin
Note
This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.