SIAH2 — the second AFF1 E3 ligase, reported only alongside SIAH1 and never separated from it
also called SIAH2 · SIAH-2 · Seven in absentia homolog 2 · E3 ubiquitin-protein ligase SIAH2
SIAH2 is a close twin of SIAH1 and was reported in the same experiment as a second enzyme that marks AFF1 for destruction. Nobody has ever tested the two separately, so we do not know whether both matter or only one does.
The same thing, for a scientist
SIAH2 (O43255, 324 aa) is a RING-finger E3 ubiquitin ligase and the paralogue of SIAH1 (Q8IUQ4, 282 aa). It was reported in the same 2004 study, in the same sentence, as binding the N-terminal portion of AF4/AFF1 and contributing to its proteasomal degradation, with the AF4::MLL reciprocal fusion protected. Like SIAH1, the contact is on the AFF1 N-terminus and is therefore present in the der(4) reciprocal product AFF1::KMT2A and absent from KMT2A::AFF1. This entry exists separately from gene-siah1 because the graph's granularity rule requires one entry per thing, and because the honest content of this entry is precisely that **SIAH2 has never been assessed apart from SIAH1** — there is no reported separation-of-function experiment, no differential affinity, and no evidence about which paralogue dominates in a B-lymphoid progenitor. SIAH2 is dispensable in DepMap (mean +0.054, 0.17% of 1,208 lines depleted).
This is a prediction, not a measurement. No one has seen this protein in this shape. The colours say how much the software trusts itself, and that is worth reading before anything else — the orange stretches are places the model is effectively saying this part has no fixed shape.
I have never read one of these pictures before
A protein is one long chain of amino acids that folds up. The ribbon traces that chain from one end to the other; it is not a wire, it is a simplification of where the backbone runs. Drag to rotate, scroll to zoom.
Domains are the stretches of chain that do a particular job, and they are what the coloured blocks above the picture mark out. Click one and the view flies to it. In this project the important question about any domain is usually whether the fusion still has it — the labels say lost where it does not.
Anything in yellow sticks is a bound small molecule, which is usually the drug.
What is and is not known, kept apart
Known 1: SIAH1 and SIAH2 both interact with the N-terminal portion of AF4/AFF1; wild-type AF4 is targeted for proteasomal degradation; the AF4::MLL fusion is protected.
Not known: whether SIAH2 alone is sufficient; whether SIAH1 alone is sufficient; whether they bind the same AFF1 surface; their relative affinities; their relative abundance in fetal-liver or pro-B progenitors, which is where t(4;11) arises; whether one paralogue buffers loss of the other.
The practical consequence is that any experiment knocking down one SIAH paralogue is uninterpretable without the other, and this is the kind of unstated redundancy that has killed target programmes elsewhere. Recording it as a known unknown is the point of the entry.
Placement in the interactome
Method: as for SIAH1 — two-hybrid discovery, co-expression and stability assays 1. Shown for: wild-type AFF1 and the reciprocal AFF1::KMT2A fusion. Which part of the fusion: the AFF1 N-terminus, which KMT2A::AFF1 does not carry.
SIAH2 is not a member of the KMT2A::AFF1 interactome. It is an interactor of wild-type AFF1 and of the reciprocal product.
DepMap: mean gene effect +0.054 across 1,208 lines, 0.17% of lines depleted, KMT2A-rearranged minus other-leukemia difference -0.047 2. Functionally invisible in a knockout screen, as expected for a degradation enzyme.
| uniprot | O43255 |
|---|---|
| gene symbol | SIAH2 |
| length AA | 324 |
| protein name | E3 ubiquitin-protein ligase SIAH2 |
| alphafold ID | AF-O43255-F1 |
| accession resolution | UniProt query gene_exact:SIAH2 AND organism_id:9606 AND reviewed:true; primary gene name read back as SIAH2 and length 324 confirmed |
| interaction evidence class | yeast two-hybrid, co-expression/stability assays; reported only jointly with SIAH1 |
| shown for fusion | yes, for the reciprocal AFF1::KMT2A product only |
| separation of function | none published — SIAH1 and SIAH2 have never been tested independently against AFF1 |
| druggability | Not a target. Listed for completeness of the AFF1 degradation axis and to record the untested paralogue redundancy. |
paralogue
{
"gene_symbol": "SIAH1",
"uniprot": "Q8IUQ4",
"length_aa": 282
}contact on fusion
{
"binds": "AFF1/AF4 N-terminal portion (no residue boundaries reported)",
"present_in_kmt2a_aff1": false,
"present_in_reciprocal_aff1_kmt2a": true
}essentiality
{
"depmap_common_essential": false,
"chronos_mean": 0.054,
"n_lines": 1208,
"fraction_lines_depleted": 0.0017,
"chronos_mean_kmt2a_rearranged": -0.0108,
"chronos_mean_other_leukemia": 0.0361,
"kmt2a_selectivity_difference": -0.0469,
"n_kmt2a_rearranged_lines": 11,
"n_other_leukemia_lines": 43,
"benchmark_men1_difference": -0.8656
}- Paralogue redundancy between SIAH1 and SIAH2 is unmeasured, which is exactly the situation in which a single-gene result fails to reproduce.
- SIAH2 is a hypoxia-responsive E3 ligase with many substrates; anything that modulated it would act far outside this axis.
- Which SIAH paralogue actually degrades AFF1 in a B-lymphoid progenitor, and do they buffer each other? A SIAH1/SIAH2 double knockdown with AFF1 protein as readout is a one-week experiment that has apparently never been done.
- Do SIAH1 and SIAH2 bind the same AFF1 surface? If they do, a single degron is the point of control; if not, there are two.
- Is the AFF1 degron conserved in AFF4, AFF2 and AFF3? If it is, SIAH activity sets the abundance of the whole SEC scaffold family, which would make it a much larger story than a t(4;11) footnote.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
SIAH2, together with SIAH1, interacts with the N-terminal portion of AF4/AFF1 and participates in targeting wild-type AF4 for proteasomal degradation, while the AF4.MLL fusion protein is protected from degradation.
Interaction of AF4 wild-type and AF4.MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology? · Bursen A, Moritz S, Gaussmann A, Moritz S, Dingermann T, Marschalek R · Oncogene 2004What this evidence cannot show
Abstract read in full; not full text. SIAH2 is named only jointly with SIAH1 — no separation-of-function experiment, no independent affinity, no residue boundaries, no structure. The abstract's own framing is a question. No replication by an independent group was retrieved.
Evidence that argues against this (1)
- The functional premise this interaction rests on - that the reciprocal AF4::MLL product drives disease - does not reproduce in human cells: AF4-MLL in human cord-blood CD34+ HSPCs gave no leukemia in 36 weeks and no serial self-renewal. Prieto C et al. 2017
- E2strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.dataset
SIAH2 has DepMap mean gene effect +0.054 across 1,208 lines with 0.17% of lines depleted, mean -0.0108 in 11 KMT2A-rearranged leukemia lines against +0.0361 in 43 other leukemia lines (difference -0.047); SIAH1 is likewise dispensable at +0.0266 mean and 2.2% depleted.
DepMap CRISPR (Chronos) gene effect via the Open Targets Platform GraphQL API, with KMT2A-rearrangement status from Cellosaurus; per-gene recomputation for this beat · Broad Institute DepMap; Cellosaurus; Open Targets Platform; analysis run by this project · Database and derived analysis 2026What this evidence cannot show
DepMap release version not stated by the API. Single-gene knockouts cannot reveal a paralogue pair that buffers each other, which is the specific redundancy at issue here; a double knockout is the experiment DepMap does not run.
Evidence that argues against this (1)
- +0.054 overall, 0.17% of lines depleted, and −0.0108 against +0.0361 across eleven and 43 lines. Every number here is a null and the entry's value is as a recorded negative. Oncofusion knowledge graph (internal analysis) 2026
- ← related toSIAH1 — the E3 ligase that degrades AFF1, and that the reciprocal AF4::KMT2A fusion escapes
paralogue pair reported only jointly; no separation-of-function experiment exists
reported with SIAH1 as binding the AFF1 N-terminal portion
- related to →KMT2A::AFF1 (MLL-AF4), t(4;11)(q21;q23)
NOT an interactor of the der(11) product
SIAH2 named with SIAH1 as acting on the N-terminal portion of AF4