Oncofusion

start / graph / gene-ubn1

Genemoderate confidence 3 of 5: One strong study, or several smaller consistent ones.Q37-histone-chaperones

UBN1 - the subunit that decides the HIRA complex is carrying H3.3 and not H3.1, by reading a single glycine

also called UBN1 · ubinuclein-1 · HIRA-binding protein · VT4 · Q9NPG3

UBN1 is the part of the H3.3 delivery machine that checks it is holding the right histone. It tells the difference between two almost identical proteins by reading one amino acid, and it also grips DNA, which is how the histone gets handed over.

The same thing, for a scientist

UBN1 (Q9NPG3, 1,134 aa) is the H3.3 specificity determinant of the HIRA complex. Its conserved **Hpc2-related domain (HRD)** binds H3.3/H4 preferentially over H3.1/H4, and crystallography plus mutation identify **H3.3 G90** as the key determinant read by conserved UBN1 residues [E1]. A separate **middle domain dimerises and binds H3/H4 without variant discrimination**, and a nearby **DNA-binding region** contributes conserved lysines - together suggesting deposition proceeds by UBN1 engaging DNA and dimerising to build an (H3.3/H4)2 tetramer [E2]. In mouse ES cells UBN1/2 are responsible for recognition and deposition of H3.3 specifically at **cis-regulatory elements** [E3]. The striking comparison is that **DAXX, the unrelated H3.3-specific chaperone of the heterochromatin route, contacts the histone at nearly identical points around H3.3 G90 by a distinct mechanism** [E1]. The same recognition problem was solved twice, independently, which is the best available structural argument that H3.3 specificity is what the two routes are actually for. In DepMap, UBN1 is neither pan-essential nor selective (difference **+0.029**, pan-essentiality **-0.130**) [E4] - the weakest dependency signal in this entire beat.

Go deeper
Why the specificity subunit is the interesting one and the least likely to matter

If you wanted to block replication-independent H3.3 deposition without touching bulk chromatin assembly, UBN1 is the obvious handle: it is the variant discriminator and it is not pan-essential. That is also the reason to be sceptical. A protein whose knockout costs a cell nothing across 1,208 lines is either redundant (UBN2 exists and the ES-cell study treats them together 3) or not rate-limiting. Paralogue buffering is the first hypothesis, and this graph has a standing rule that a paralogue split is only real if the silent paralogue is expressed - which for UBN1/UBN2 has not been checked here.

The entry is written so the next cycle can close that cheaply: the test is UBN2 expression in KMT2A-rearranged lines and a double knockout, neither of which exists in this disease.

The disease intersection is empty, and the emptiness is shallow

UBN1 OR ubinuclein returns 31 records in total across all of PubMed. There is no leukaemia literature. The one blood-adjacent record found on title check is an activation-induced cytidine deaminase interaction study in B cells (PMID 37949972), which is a different question but is the only place UBN1 and a lymphoid cell meet in print; it is recorded here as a bounded rejection, not cited as evidence.

This is a thin literature, not a contested one. Nothing has been tried and failed; the protein has been studied structurally by essentially one group and biologically by a handful.

Facts and figures
uniprotQ9NPG3
gene symbolUBN1
length AA1134
paralogueUBN2
complexprotein-huca-complex
functionH3.3 variant specificity determinant (HRD reads H3.3 G90); DNA binding; dimerisation
total pubmed records all topics31
kmt2a literature records0
depmap
other_leukaemia_mean-0.186other_leukaemia_mean: -0.1863index_mean-0.157index_mean: -0.157pan_essentiality-0.130pan_essentiality: -0.1299difference0.029difference: 0.0293n_index11.0n_index: 11
depmap — the numbers behind the chart
{
  "index_mean": -0.157,
  "other_leukaemia_mean": -0.1863,
  "difference": 0.0293,
  "pan_essentiality": -0.1299,
  "n_index": 11
}
depmap kmt2a selectivity
{
  "chronos_mean_kmt2a_rearranged": -0.157,
  "chronos_mean_other_leukaemia": -0.1863,
  "difference": 0.0293,
  "pan_essentiality_all_lines": -0.1299,
  "selectivity_rank": 12797,
  "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."
}
How this could bite us back
  • The variant-specificity subunit is the most attractive target in the H3.3 pathway and has the least evidence of being limiting; a selective UBN1 inhibitor could be perfectly engineered and do nothing.
  • UBN2 is an immediate resistance mechanism requiring no mutation - paralogue up-regulation, the compensation route this graph has documented four times.
  • Any block on H3.3 deposition slows nucleosome turnover, and slower turnover means slower clearance of H3K79 methylation, so this target is predicted to antagonise rather than complement a DOT1L inhibitor.
Still open
  1. Is UBN2 expressed in KMT2A-rearranged leukaemia lines? Until that is checked, UBN1's flat DepMap profile is uninterpretable and the graph's paralogue rule is unsatisfied.
  2. Can the UBN1-HRD/H3.3 G90 interface be drugged selectively against the DAXX/H3.3 interface, which contacts nearly the same surface by a different mechanism? That is the only route to pharmacologically separating the gene-body and heterochromatin H3.3 pathways.
  3. Does UBN1 reach PML nuclear bodies independently of HIRA, or only as part of the complex? The Sp100A study reports UBN1 mislocalising together with HIRA and ASF1A, which does not distinguish these.
Every source behind this entry (5)
  1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

    The conserved UBN1 Hpc2-related domain preferentially binds H3.3/H4 over H3.1/H4; X-ray crystallography and mutation identify conserved UBN1-HRD residues and H3.3 G90 as the determinants of specificity, and comparison with the unrelated H3.3-specific chaperone DAXX reveals nearly identical points of chaperone-histone contact near H3.3 G90 achieved by a distinct mechanism.

    Ubinuclein-1 confers histone H3.3-specific-binding by the HIRA histone chaperone complex. · Ricketts MD, Frederick B, Hoff H, et al. · Nature Communications 2015
    PMID 26159857DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Isolated-domain crystallography and in vitro binding: established for the interaction studied, and a preference measured on fragments is not a demonstration that the intact complex discriminates variants in a cell. No residue spans are stored here because they were not derived by aligning a fetched entity sequence to a freshly fetched UniProt sequence, which is this project's requirement.

    Evidence that argues against this (1)
    • In mouse ES cells the deposition function of UBN1/2 is specific to cis-regulatory elements rather than to H3.3 everywhere, so in-vitro variant specificity and in-vivo targeting are different properties and the structural result does not establish the second. Xiong C et al. 2018
  2. E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    UBN1 has a conserved central middle domain that forms dimers and binds H3/H4 without discriminating H3.1 from H3.3, plus a DNA-binding domain located between the HRD and the middle domain that binds DNA through conserved lysines; together these suggest a deposition mechanism in which UBN1 associates with DNA and dimerises to form an (H3.3/H4)2 heterotetramer before chromatin deposition.

    The HIRA histone chaperone complex subunit UBN1 harbors H3/H4- and DNA-binding activity. · Ricketts MD, Dasgupta N, Fan J, et al. · Journal of Biological Chemistry 2019
    PMID 31040182DOI
    What this evidence cannot show

    Abstract read from efetch 2026-09-20; full text not read. Fragment biochemistry; the middle domain's helical structure is predicted rather than solved, and the mechanism is explicitly offered as a suggestion. Same laboratory as E1, so these are not independent observations.

    Evidence that argues against this (1)
    • A 2024 study from the same group attributes HIRA-complex deposition to histone tetramerization and histone-DNA binding as the driving forces, which reorders the steps this proposal puts UBN1 at the head of. Vogt A et al. 2024
  3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

    UBN1 and UBN2 of the HIRA complex are responsible for recognition and deposition of H3.3 at cis-regulatory elements of genes in mouse embryonic stem cells.

    PMID 30285846DOI
    What this evidence cannot show

    Title and record read from efetch 2026-09-20; the abstract was skimmed and the full text was not read. Mouse ES cells only. **The study treats UBN1 and UBN2 together, which is the reason this entry cannot say what UBN1 alone does** - and that redundancy is the most likely explanation for UBN1's flat DepMap profile.

    Evidence that argues against this (1)
    • If UBN1 and UBN2 are interchangeable then no single-gene result, including this one, separates them, and any therapeutic argument built on UBN1 is buffered by construction. The graph's own paralogue rule applies: the split is only real if the silent paralogue is expressed, and that has not been checked in leukaemia. Oncofusion knowledge graph (internal analysis) 2026
  4. E4moderate confidence 3 of 5: One strong study, or several smaller consistent ones.dataset

    In DepMap CRISPR gene effect, UBN1's mean effect in 11 KMT2A-rearranged leukaemia lines is -0.157 against -0.186 in 43 other leukaemia lines, a difference of +0.029 (i.e. very slightly LESS required in the index arm), at a pan-essentiality of -0.130 across 1,208 lines.

    What this evidence cannot show

    Run 2026-09-20. A near-zero pan-essentiality means the knockout is close to neutral in most lines, so the group difference is a difference between two numbers that are both approximately nothing. This is reported as a negative result, which is what it can support; it is not evidence that UBN1 does nothing, only that its loss does not reduce fitness in a two-week pooled screen.

    Evidence that argues against this (1)
    • UBN2 exists and the only in-vivo deposition study treats UBN1 and UBN2 together, so a single-gene CRISPR screen is expected to return nothing for a buffered paralogue pair regardless of the protein's importance. Xiong C et al. 2018
  5. E5established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

    UBN1 is UniProt Q9NPG3 (UBN1_HUMAN), ubinuclein-1, also called HIRA-binding protein and protein VT4, 1,134 amino acids, with no alias symbols listed in the reviewed record.

    UniProtKB Q9NPG3 (UBN1_HUMAN), Ubinuclein-1, 1134 aa · UniProt Knowledgebase, reviewed (Swiss-Prot) 2026
    What 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 UBN1. The absence of alias symbols in the record does not mean the literature uses none - 'ubinuclein' is the commonest spelled-out form and was searched separately.

    Evidence that argues against this (1)
    • UBN1's closest functional relative UBN2 is a separate gene and a separate record, and the accession check cannot detect a paper that studied one and named the other. The paralogue trap this project logged for CSNK2A1/CSNK2A2 is the same shape. US National Library of Medicine 2026
Connected to