LIG3 (human, P49916) review notes

Literature search (manual; no deep-research provider available)

Sources checked:
- All GOA-cited PMIDs, cached with just fetch-gene-pmids human LIG3 (13 papers).
- PubMed E-utilities searches (2026-11-04): "Gao Y[au] DNA ligase III essential
mitochondrial Nature 2011" -> PMID:21390131, PMID:21390132; "Wang H[au] DNA ligase III
backup pathways nonhomologous end joining 2005" -> PMID:15899791; "Della-Maria J[au]
ligase III alternative end joining" -> PMID:21816818; "Simsek D[au] ligase III end
joining 2011" -> PMID:21655080; "Lu G[au] ligase III alternative end joining 2016
microhomology" -> PMID:26787905. All fetched into publications/.
- Reactome cached entries for LIG3 reactions (BER, MMEJ, NER ligation, mtDNA ligation).
- UniProt P49916 record.

Key findings

• One gene, two compartments. Isoform 1 (P49916-1) carries an N-terminal mitochondrial
  transit peptide; isoform 3 (alpha, P49916-3) starts at the downstream ATG and is nuclear;
  isoforms 2/4 (beta, germ-cell splice form) lack the XRCC1-binding BRCT
  PMID:10207110.
• Activity: ATP-dependent nick sealing; the PARP-like ZnF senses nicks/ends
  [PMID:20518483 "The collective results support a \"jackknife model\" in which the ZnF loads
  ligase III onto nicked DNA and conformational changes deliver DNA into the active site."].
  LigIIIalpha/XRCC1 and LigIIIbeta join nicked and linear duplex substrates
  PMID:19589734.
• Essential role is mitochondrial: PMID:21390132; PMID:21390131. Human biallelic variants cause MNGIE-like mtDNA depletion
  PMID:33855352.
• mtDNA replication: Okazaki-fragment ligation PMID:21878356. The
  GOA IMP row for this paper uses "negative regulation of mitochondrial DNA replication",
  which inverts the sign of the knockdown result (knockdown attenuated recovery of mtDNA
  copy number). Recorded as a source defect (CACAO).
• mtBER: PMID:24674627.
• Nuclear BER/SSBR with XRCC1 (Reactome; PMID:33087283 review), redundant with LIG1 in
  mouse cells (PMID:21390131).
• Alt-NHEJ/MMEJ: PMID:15899791; PMID:21816818; translocations reduced
  without nuclear Lig3 PMID:21655080; LIG1 can substitute for some A-EJ PMID:26787905.
• Not in V(D)J recombination: LIG3 cannot complement LIG4-null pre-B cells (PMID:9809069),
  supporting the NOT annotation.
• Context: telomere end-joining pathway choice (module and GO-CAM review proposed in ai4curation/ai-gene-review#5904; not on this branch and not used as evidence). The placement of LIG3 (with PARP1)
  in the alternative-NHEJ route at telomeres lacking POT1-TPP1 rests on PMID:28216226 ("interaction of
  de-phosphorylated NBS1S432 with TRF2 promotes A-NHEJ mediated repair of telomeres lacking POT1-TPP1") and
  the LIG3 alt-NHEJ literature above.

Curation decisions of note

• GO:0003909 rows MODIFY -> GO:0003910 DNA ligase (ATP) activity.
• Reactome "Homology Directed Repair" TAS for HR -> MODIFY to alt-NHEJ (MMEJ is grouped
  under HDR in Reactome but is not homologous recombination).
• ARBA "mitochondrion organization" -> MODIFY to mitochondrial DNA metabolic process
  (GO:0000002 mitochondrial genome maintenance is obsolete).
• ARBA "negative regulation of DNA metabolic process" REMOVE (no supporting evidence).
• Bare protein-binding IPI rows REMOVE per policy.