SIR4 curation notes

2026-09-02 Update

Audited existing_annotations for oversights (this is a companion fix to the same
issue found and fixed in SIR2 and SIR3).

• GO:0006303 (double-strand break repair via nonhomologous end joining), IMP,
  PMID:9501103: was marked MARK_AS_OVER_ANNOTATED ("SIR4 is not a direct
  participant in the NHEJ catalytic machinery... this is an indirect function...
  overstates SIR4's role"). But the cited paper's abstract reports a direct
  functional assay, not an inference: "using an in vivo plasmid rejoining assay,
  we demonstrate that SIR2, SIR3 and SIR4, three genes shown previously to
  function in TPE, are essential for Ku-dependent DSB repair" PMID:9501103. SIR4 is not core NHEJ catalytic
  machinery, so the function remains secondary/non-core, but MARK_AS_OVER_ANNOTATED
  mischaracterizes directly-demonstrated genetic evidence as likely spurious
  over-annotation. Changed action to KEEP_AS_NON_CORE, consistent with the same
  fix applied to SIR2 and SIR3 for the identical annotation/reference.
• All other annotations reviewed; no other genuine, evidence-backed oversights
  found.

2026-09-05 Update — corrects the 2026-09-02 entry above

Review feedback on PR #2946 correctly pointed out that the 2026-09-02 rationale
conflated a direct assay with a direct role, and that two claims in it
were wrong. Both are corrected here.

1. The role is indirect, and the follow-up literature says so explicitly.
Boulton & Jackson's assay is direct, but the sir end-joining defect is largely
a consequence of mating-type derepression, not of SIR4 acting at the break. In
sir mutants HML/HMR are expressed, the cell adopts an a/alpha pseudo-diploid
identity, and a1/alpha2 represses the haploid-specific NHEJ factor NEJ1
PMID:10421582 PMID:11676923. The residual direct contribution is small: with haploid identity
held constant, sir deletions reduce chromosomal NHEJ only two- to threefold and
leave plasmid end-joining unaffected PMID:10421582.

The decisive experiment is Kegel et al.'s rescue, whose sir panel explicitly
includes Sir4p: constitutive Nej1p expression "completely rescued the defect in
NHEJ, thus showing that Sir proteins per se were dispensable for NHEJ"
PMID:11676923. So SIR4 is not a participant in end-joining at all — it acts
permissively upstream, silencing HML/HMR so that NEJ1 stays expressed.

Action therefore changed from KEEP_AS_NON_CORE to MODIFY, proposing
GO:2001032 regulation of double-strand break repair via nonhomologous end
joining (verified via OLS; not obsolete). The general regulation term is used
rather than the directional GO:2001034 because the role is permissive rather
than actively modulating. KEEP_AS_NON_CORE was rejected because it retains the
participant term GO:0006303, which the Kegel rescue contradicts.

2. The "already fixed in SIR2/SIR3" claim was not true when written. At the
time of the 2026-09-02 entry both PRs were still open. Current state on main:
SIR3 (#2944) merged 2026-09-05 with exactly the MODIFY → GO:2001032
adjudication adopted here; SIR2 (#2942) is still open and still carries
REMOVE. The merged SIR3 entry explicitly flags SIR4 and SIR2 as needing
reconciliation with its rationale — this update does that for SIR4. SIR2 remains
outstanding.

Deliberate divergence from the review's two suggested options. The review
offered (1) keep KEEP_AS_NON_CORE with a corrected reason, or (2) keep
MARK_AS_OVER_ANNOTATED with the correct mechanism. Neither was taken, because
the review was written on 2026-09-02, three days before SIR3 merged, and the
merged SIR3 decision settles the identical annotation/evidence/reference triple
on MODIFY → GO:2001032. Adopting the same outcome keeps the three Sir entries
consistent rather than introducing a third adjudication of one experiment.

Not changed (out of shepherd scope): SIR4-ANNOTATION-ACTIONS.tsv and
SIR4-CURATION-SUMMARY.md still record the old action and the repudiated
telomere-stabilization rationale, as the review's 🔵 item noted. These are
hand-maintained companion artifacts outside the curation file set, and are left
for a curator to update or delete.