Esl1 (YIL151C) is a 1118-residue budding-yeast Est1/SMG-family protein with a central 14-3-3-like Est-one-homology domain and a C-terminal PIN domain containing conserved acidic residues. It is closely related to Esl2 and structurally related to metazoan SMG5/6 proteins. Single and double deletions did not cause accumulation of the two tested nonsense-mediated decay substrates, or defects in the tested telomere-length, senescence and subtelomeric-silencing assays. These findings distinguish its detected physiological effects from canonical NMD and telomere maintenance, while leaving direct nucleic-acid binding and dispensable complex association unresolved. The double mutant shows inappropriate expression of nutrient-responsive genes, genetic interactions with Rim101-pathway components and Trf4, increased respiratory-deficient colony formation, and altered genotoxin responses. Some genotoxin phenotypes depend on conserved PIN residues, whereas most tested transcript-expression changes do not. Its direct substrates, molecular mechanism and subcellular distribution remain unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000184 nuclear-transcribed mRNA catabolic process, nonsense-mediated decay | IBA GO_REF:0000033 | REMOVE | Summary: Single and double esl mutants do not accumulate ade2-1 or pre-CYH2 RNA under the tested conditions, unlike the upf1 control. Reason: The actual PAINT tree supports ancestral NMD inheritance at PTN000403280. Target-specific measurements of two NMD substrates in single and double mutants provide concrete evidence against a detectable canonical NMD contribution and justify retaining REMOVE. This is a scoped experimental conflict, not proof that every substrate, condition or residual activity has been excluded, and not a claim that the target inherited an unrelated IRD loss. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000403280 SUPPORTS SOURCE BUT NOT TARGET Actual target descent is verified. Two target NMD-substrate assays challenge transfer under the tested conditions; they do not establish a universal mechanistic loss. Supporting Evidence: PMID:23893744 based on these two independent assays, ESL1 and ESL2 do not seem to have NMD-related functions file:yeast/ESL1/ESL1-paint-lineage.md All four inherited annotations originate at PTN000403280 and are still positive on target leaf PTN007651903. |
| GO:0005697 telomerase holoenzyme complex | IBA GO_REF:0000033 | UNDECIDED | Summary: Inherited telomerase holoenzyme association is not directly assayed by the telomere-maintenance experiments. Reason: The actual tree places Esl1 below the positively annotated ancestor PTN000403280, and the related IRD-loss node PTN008560932 is outside its lineage. Extensive target telomere-length, senescence/alternative-lengthening, silencing and telomeric-transcript negatives challenge the expected physiological consequence of this inherited function, but do not experimentally negate telomerase holoenzyme association. Dispensable association or binding could remain. Retain UNDECIDED after focused adjudication: the report does not establish a target binding/association loss. Its IBA-only, zero STRING experimental score and low global-identity arguments cannot replace the verified ancestral placement. Its extrapolation from NMD-substrate negatives to telomerase functions is not valid. Primary PMID:22544908 provides a positive KlEst1 binding comparator but does not test Esl1. Expert review of the ancestral interface and direct target assays remain needed. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000403280 UNRESOLVED Target descent and ancestral assertion are verified. Direct target physiological negatives create an indirect conflict that does not establish loss of binding or complex association. Supporting Evidence: PMID:23893744 Esl1 and Esl2 are not required for telomerase-dependent or alternative telomere maintenance mechanisms file:yeast/ESL1/ESL1-paint-lineage.md The telomere panel tested length, senescence/alternative lengthening, subtelomeric silencing and telomeric transcript abundance. |
| GO:0042162 telomeric repeat DNA binding | IBA GO_REF:0000033 | UNDECIDED | Summary: Inherited telomeric-repeat DNA binding is not directly assayed by the telomere-maintenance experiments. Reason: The actual tree places Esl1 below the positively annotated ancestor PTN000403280, and the related IRD-loss node PTN008560932 is outside its lineage. Extensive target telomere-length, senescence/alternative-lengthening, silencing and telomeric-transcript negatives challenge the expected physiological consequence of this inherited function, but do not experimentally negate telomeric-repeat DNA binding. Dispensable association or binding could remain. Retain UNDECIDED after focused adjudication: the report does not establish a target binding/association loss. Its IBA-only, zero STRING experimental score and low global-identity arguments cannot replace the verified ancestral placement. Its extrapolation from NMD-substrate negatives to telomerase functions is not valid. Primary PMID:22544908 provides a positive KlEst1 binding comparator but does not test Esl1. Expert review of the ancestral interface and direct target assays remain needed. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000403280 UNRESOLVED Target descent and ancestral assertion are verified. Direct target physiological negatives create an indirect conflict that does not establish loss of binding or complex association. Supporting Evidence: PMID:23893744 Esl1 and Esl2 are not required for telomerase-dependent or alternative telomere maintenance mechanisms file:yeast/ESL1/ESL1-paint-lineage.md The telomere panel tested length, senescence/alternative lengthening, subtelomeric silencing and telomeric transcript abundance. |
| GO:0070034 telomerase RNA binding | IBA GO_REF:0000033 | UNDECIDED | Summary: Inherited telomerase RNA binding is not directly assayed by the telomere-maintenance experiments. Reason: The actual tree places Esl1 below the positively annotated ancestor PTN000403280, and the related IRD-loss node PTN008560932 is outside its lineage. Extensive target telomere-length, senescence/alternative-lengthening, silencing and telomeric-transcript negatives challenge the expected physiological consequence of this inherited function, but do not experimentally negate telomerase RNA binding. Dispensable association or binding could remain. Retain UNDECIDED after focused adjudication: the report does not establish a target binding/association loss. Its IBA-only, zero STRING experimental score and low global-identity arguments cannot replace the verified ancestral placement. Its extrapolation from NMD-substrate negatives to telomerase functions is not valid. Primary PMID:22544908 provides a positive KlEst1 binding comparator but does not test Esl1. Expert review of the ancestral interface and direct target assays remain needed. Propagation Review Root cause: UNRESOLVED Sources checked: PANTHER:PTN000403280 UNRESOLVED Target descent and ancestral assertion are verified. Direct target physiological negatives create an indirect conflict that does not establish loss of binding or complex association. Supporting Evidence: PMID:23893744 Esl1 and Esl2 are not required for telomerase-dependent or alternative telomere maintenance mechanisms file:yeast/ESL1/ESL1-paint-lineage.md The telomere panel tested length, senescence/alternative lengthening, subtelomeric silencing and telomeric transcript abundance. |
| GO:0003674 molecular_function | ND GO_REF:0000015 | KEEP AS NON CORE | Summary: ND placeholder records the absence of a specific experimental molecular-function assignment. Reason: Retain the curator-supplied placeholder. It is not an assertion that inferred molecular functions or locations are biologically absent. Supporting Evidence: file:yeast/ESL1/ESL1-deep-research-falcon.md Whether the ESL1 PIN domain retains catalytic activity or functions as an inactive scaffold (analogous to SMG5) remains to be experimentally determined. |
| GO:0005575 cellular_component | ND GO_REF:0000015 | KEEP AS NON CORE | Summary: ND placeholder records the absence of a specific experimental localization assignment. Reason: Retain the curator-supplied placeholder. It is not an assertion that inferred molecular functions or locations are biologically absent. |
| GO:0008150 biological_process | ND GO_REF:0000015 | ACCEPT | Summary: Retain the curator-supplied ND process placeholder while the mechanistic basis of the target phenotypes remains unresolved. Reason: Transcriptomic and genetic findings motivate adaptive-response and gene-expression hypotheses, but the step performed by Esl1 is not established. Replacing the root term solely to align authored core assertions would manufacture a process claim from phenotype alone. Supporting Evidence: PMID:23893744 Esl1 and Esl2 contribute to the regulation of adaptive gene expression responses of environmental sensing pathways |
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Download this section (compressed HTML)Q: Is Esl1 a catalytically active endoribonuclease in vivo, and if so, what RNAs does it cleave during nutrient/pH adaptation?
Q: Does the 14-3-3-like Est-one-homology domain of Esl1 mediate a regulatory protein-protein interaction analogous to the SMG5/6βUPF1 interaction in metazoa?
Q: What is the subcellular localization of Esl1, and does it change with nutrient or pH conditions?
Q: Does Esl1 physically associate with telomerase holoenzyme, telomeric-repeat DNA or TLC1 RNA despite the normal tested telomere-maintenance phenotypes? Reconcile the verified PAINT ancestry with the direct functional negatives. The focused report is incorporated but does not resolve the physical-capacity question; its absence-of-evidence arguments do not justify REMOVE or a NOT assertion.
Q: What molecular step does Esl1 itself perform in the observed gene-expression/nutrient-adaptation phenotype, and does it support a process annotation independently of double-mutant transcriptome effects? The two previous authored NEW process rows and speculative custom MF proposal are withdrawn pending that evidence.
Experiment: Perform RIP-seq/CLIP-seq on tagged Esl1 under high- and low-glucose and alkaline conditions, and compare mRNA half-lives in wild-type, esl1 esl2, and nuclease-dead alleles.
Hypothesis: Esl1 regulates a specific set of nutrient/pH-responsive mRNAs via its PIN domain.
Experiment: Epistasis and interaction analysis of Esl1 with Rim101-pathway components (Rim8, Dfg16, Rim13, Rim20) under alkaline and low-glucose stress, with transcriptome readout.
Hypothesis: Esl1 acts in a pathway parallel to Rim101 in environmental adaptation.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The direct molecular activity of Esl1 is undetermined. It is unknown whether Esl1 is a catalytically active endoribonuclease in vivo, and if so what its RNA substrates are; the conserved PIN catalytic residues are intact but no biochemical nuclease assay of Esl1 has been reported, and the characterized adaptive gene-expression phenotype is largely independent of PIN catalytic integrity.
OPEN BIOLOGY MF_DARK
What is known: Esl1 has an EOH/14-3-3-like region and a PIN domain with conserved acidic residues; the experimentally generated esl1-nd allele changes D952 and E982. SMG6 provides an active-nuclease comparator, whereas the related SMG5 protein is catalytically impaired. The two assayed NMD substrates and tested telomere-maintenance outcomes were normal in single/double mutants. These data do not directly test telomeric binding or complex association. A bleomycin-response phenotype depends on the altered PIN residues, without establishing purified Esl1 nuclease activity.
Significance: Identifying direct substrates and biochemical activity would explain the relationship between the conserved Est1/SMG architecture and the adaptive-expression/genome-stability phenotypes.
What would resolve it: In vitro endoribonuclease assays with purified Esl1 and its PIN domain; CLIP/RIP-style identification of bound RNAs; comparison of wild-type vs nuclease-dead alleles for each phenotype.
Provenance (the field's own admissions):
Gap: The molecular partners and substrates of Esl1 are unknown, including any protein-protein interaction mediated by its 14-3-3-like EOH domain (the domain that in metazoan SMG5/6 engages the NMD factor UPF1) and any direct link to the Rim101 pH-sensing machinery.
OPEN BIOLOGY MF_DARK
What is known: A large-scale two-hybrid interaction with Mdt1/Pin4 and genetic interactions with rim8, dfg16 and trf4 provide candidate relationships. They do not establish which EOH/PIN interaction or substrate accounts for the physiological phenotype.
Significance: Identifying an Esl1 interaction partner would reveal the mechanism connecting the Est1/SMG fold to nutrient/pH-adaptive gene expression and clarify whether the EOH domain retains a regulatory protein-interaction function analogous to its metazoan counterparts.
What would resolve it: Affinity-purification/mass-spectrometry and proximity-labeling of tagged Esl1; targeted tests of physical interaction with Rim101-pathway and TRAMP components.
Provenance (the field's own admissions):
Gap: The ESL1-specific (non-redundant) contribution and in vivo biological role are not resolved, because almost all phenotypes are stronger in esl1 esl2 double mutants and the transcriptome signature was measured only in the double mutant.
OPEN BIOLOGY BP_DARK
What is known: esl1 single mutants show telomere/NMD-negative results and specific synthetic-sick interactions (with FUS3, DAL81, SNX4, and synthetic-lethal with TRF4), and the pair is redundant for the adaptive gene-expression, mitochondrial-stability and genotoxin phenotypes; but no ESL1-only phenotype defines its unique function.
Significance: Distinguishing the individual roles of ESL1 and ESL2 is needed to know whether ESL1 has a dedicated regulon or is fully redundant with its paralog.
What would resolve it: Condition- and stress-resolved transcriptomics and phenotyping of esl1 single mutants (including nuclease-dead), with direct comparison to esl2 and the double mutant.
Provenance (the field's own admissions):
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