CABIN1 - a 2,220-residue calcineurin inhibitor that is also a full member of the H3.3 chaperone complex, and nobody has asked which job matters in blood
also called CABIN1 · KIAA0330 · cabin-1 · calcineurin-binding protein 1 · calcineurin inhibitor · Q9Y6J0
CABIN1 has two unrelated day jobs: it blocks a signalling enzyme that switches on immune genes, and it is part of the machine that loads replacement histones onto active genes. Which of the two matters in a leukaemia cell has never been asked.
The same thing, for a scientist
CABIN1 (Q9Y6J0, 2,220 aa) is the fourth subunit of the HUCA complex and the likely orthologue of yeast Hir3p; HIRA and CABIN1 interact at endogenous levels, the quaternary complex assembles from recombinant proteins, CABIN1 participates in senescence heterochromatinisation, and in proliferating cells HIRA and CABIN1 regulate overlapping gene sets enriched in H3.3 [E1]. Separately and much better known, CABIN1 is **calcineurin-binding protein 1**, a calcineurin inhibitor that restrains NFAT signalling - which is its UniProt protein name [E2]. **The two functions have never been separated in a haematopoietic cell, and in a lymphoid disease that is not a footnote.** Calcineurin-NFAT is a lymphocyte signalling axis; the index disease of this graph is infant B-ALL. An entry that filed CABIN1 only as a histone chaperone would be as incomplete as `gene-daxx`'s own caveat about DAXX-as-apoptotic-adaptor says that entry is. DepMap gives no selectivity worth reporting: difference -0.104, pan-essentiality -0.151 [E3].
Two proteins in one gene, and the risk that comes with it
This project has a documented failure mode where an entry inherits a framing from the beat that wrote it. CABIN1 is the clearest case in this beat: it arrives here because of HUCA, and everything about the name, the length and the older literature says calcineurin.
What can be said honestly:
- As a chaperone subunit, CABIN1 is established as a functional member with an overlapping, H3.3-enriched gene set 1. It is not a passenger.
- As a calcineurin inhibitor, the reviewed record names it so 2 and there is a substantial immunology literature that this beat did not read and does not cite.
- Which function a 2,220-residue protein is performing in any given experiment is not determined by the experiment, unless the experiment used a separation-of-function allele. None of the chaperone work cited here did.
The practical consequence: a CABIN1 knockout phenotype in a lymphoid cell is uninterpretable between the two functions, and no reader should treat one as controlled for the other.
| uniprot | Q9Y6J0 |
|---|---|
| gene symbol | CABIN1 |
| length AA | 2220 |
| complex | protein-huca-complex |
| second function | calcineurin-binding protein / calcineurin inhibitor (NFAT signalling) |
| yeast orthologue | Hir3p (weak homology) |
depmap — the numbers behind the chart
{
"index_mean": -0.2305,
"other_leukaemia_mean": -0.1264,
"difference": -0.1041,
"pan_essentiality": -0.1507,
"myeloid_difference": -0.0906,
"lymphoid_difference": -0.1353,
"n_index": 11
}depmap kmt2a selectivity
{
"chronos_mean_kmt2a_rearranged": -0.2305,
"chronos_mean_other_leukaemia": -0.1264,
"difference": -0.1041,
"pan_essentiality_all_lines": -0.1507,
"selectivity_rank": 1052,
"rank_denominator": 17728,
"provenance": "Joined 2026-09-21 from analyses/depmap-kmt2a-selective-scan-full (generated 2026-09-19T10:12:06Z), the project's own genome-wide scan over 11 KMT2A-rearranged and 43 other leukaemia DepMap lines. NOT re-fetched and NOT independent of that scan: every caveat it carries applies here, including that the KMT2A-rearranged arm is a small number of lines drawn from nine individuals, that the rank denominator is 17,728 genes, and that a difference is not a dependency. Added because only 26 of 308 gene entries carried this number, which made any KMT2A-selectivity question answerable for 8% of the corpus.",
"how_to_read": "A negative difference means MORE required in KMT2A-rearranged lines than in other leukaemia lines. A rank near 17,728 is ANTI-selective. Neither is evidence of a fusion-driven dependency on its own: check pan_essentiality_all_lines before calling anything selective, and note that a paralogue-redundant gene can score near zero for reasons that have nothing to do with this disease - see ana-the-paralogue-redundancy-excuse-is-not-tested-and-my-proxy-decided-the-answer."
}- Targeting CABIN1 would perturb calcineurin-NFAT signalling in lymphocytes at the same time as histone deposition; in a lymphoid disease those are not separable side effects, they are two on-target effects with different toxicities.
- A 2,220-residue scaffold with two unrelated functions is a poor small-molecule target and an ambiguous genetic one - a knockout result would not tell you which pathway produced it.
- In a lymphoid leukaemic cell, is a CABIN1 phenotype a chaperone phenotype or a calcineurin/NFAT phenotype? No separation-of-function allele has been used in any blood system.
- Does CABIN1 contribute anything biochemically to H3.3 deposition, or is it a scaffold-associated subunit whose loss is tolerated because the deposition activity lives in UBN1 and HIRA?
- Is the calcineurin-NFAT arm of CABIN1 relevant to infant B-ALL at all? This beat did not read that literature and records the omission rather than guessing.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper
HIRA and CABIN1 interact at ectopic and endogenous levels of expression; the quaternary HIRA/UBN1/CABIN1/ASF1a complex assembles from recombinant proteins with HIRA as scaffold; CABIN1, like HIRA, UBN1 and ASF1a, is involved in heterochromatinisation of the genome of senescent human cells; and in proliferating cells HIRA and CABIN1 regulate overlapping sets of genes enriched in H3.3. CABIN1 is the likely orthologue of yeast Hir3p.
Human CABIN1 is a functional member of the human HIRA/UBN1/ASF1a histone H3.3 chaperone complex. · Rai TS, Puri A, McBryan T, et al. · Molecular and Cellular Biology 2011What this evidence cannot show
Abstract read from efetch 2026-09-20; full text not read. Human fibroblasts and recombinant reconstitution; no haematopoietic cell and no leukaemia. 'Functional member' is established for complex membership and for the overlapping gene set, not for a specific mechanistic step - the paper does not assign CABIN1 a biochemical activity within deposition. The orthology to Hir3p is inferred from weak homology, which the abstract states.
Evidence that argues against this (1)
- The subunit whose loss should matter most for deposition is the specificity determinant, and that is UBN1, not CABIN1; nothing in the HUCA structural literature assigns CABIN1 a histone- or DNA-binding role. An entry treating CABIN1 as a deposition factor rather than as a complex member is claiming more than has been shown. Ricketts MD et al. 2015
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
CABIN1 is UniProt Q9Y6J0 (CABIN_HUMAN), calcineurin-binding protein cabin-1, also named calcineurin inhibitor, 2,220 amino acids, with alias symbol KIAA0330.
UniProtKB Q9Y6J0 (CABIN_HUMAN), Calcineurin-binding protein cabin-1, 2220 aa · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026What this evidence cannot show
Fetched 2026-09-20 with `gene_primary` requested and read back per rule 62: exactly one reviewed human record, primary gene name CABIN1. The protein NAME in the reviewed record is the calcineurin function, not the chaperone function, which is itself the point this entry makes.
Evidence that argues against this (1)
- A database protein name records which function was characterised first, not which dominates. Using the name as evidence about relative importance would repeat the error this project logged for gnomAD constraint and ChEMBL activity counts - a true database fact read as decision-relevant when it is not. Rai TS et al. 2011
- E3moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset
In DepMap CRISPR gene effect, CABIN1's mean effect in 11 KMT2A-rearranged leukaemia lines is -0.231 against -0.126 in 43 other leukaemia lines, a difference of -0.104, at a pan-essentiality of -0.151 across 1,208 lines; myeloid difference -0.091, lymphoid difference -0.135.
Is any histone chaperone or variant-exchange gene selectively required in KMT2A-rearranged leukaemia lines, and does the answer survive a lineage split? · Oncofusion knowledge graph (internal analysis) 2026What this evidence cannot show
Run 2026-09-20. A difference of -0.104 is below this project's -0.15 selectivity convention and no permutation null was computed. Reported so that the number exists and is not re-derived as a discovery next cycle. The lymphoid half is 4 lines.
Evidence that argues against this (1)
- CABIN1's difference is at least consistent in sign across the lineage split, unlike HIRA's, which is a weak point in its favour - but consistency across two underpowered halves is not evidence, and this project's sibling shortlist of much larger differences did not survive a 50,000-label permutation null. Oncofusion knowledge graph (internal analysis) 2026
fourth subunit; yeast Hir3p orthologue
interacts at ectopic and endogenous expression; overlapping H3.3-enriched gene set