DNASE2 (O00115) curation notes

No deep-research provider was available for this session; these notes were
assembled manually from cached primary literature (Europe PMC searches, all PMIDs
verified and cached with ai-gene-review fetch-pmid).

Identity and biochemistry

• Human DNase II (DNase II alpha), 360 aa, signal peptide + lysosomal acid
  endonuclease; cDNA cloned in 1998 PMID:9446563
  PMID:9812984.
• Expressed ubiquitously PMID:9446563.
• Catalytic domain belongs to the phospholipase D superfamily (two HKD-like
  half-sites) PMID:16150810.
• Recombinant human wild-type DNase II digests plasmid DNA at pH 5; patient
  variants (G116A, D121V, exon-4 deletion) lose activity; patient fibroblasts lack
  activity, rescued by WT cDNA PMID:29259162.
• A 2024 report claims salivary/purified DNase II also digests RNA in mildly acidic
  conditions PMID:39329709.
  Single report; not adopted as a GO function here.

Localization

• Lysosome; mouse DNase II processed (cathepsin L-dependent) and activated in
  lysosomes, detected in macrophage lysosomes PMID:23516607. Note the abstract describes the
  mouse protein; GOA records an IDA on human O00115 from this paper.
• Porcine enzyme: processing in lysosomes but not needed for activation PMID:19292869.
• Soluble luminal enzyme: signal peptide, no transmembrane segment, acid pH optimum,
  luminal processing -> lysosomal lumen (IC, added as NEW).
• Also secreted (saliva, PMID:39329709) and detected in urinary/prostatic exosome
  proteomics (PMID:23533145, HDA) - non-core.

Biological roles (mostly mouse genetics)

• Digests DNA of engulfed apoptotic cells in macrophage lysosomes/phagolysosomes
  PMID:12524536.
• Digests nuclei expelled from erythroid precursors in fetal liver macrophages; Dnase2-/-
  mice die of anemia PMID:11375492; acts non-cell-autonomously from macrophages.
  The anemia is an interferon-driven consequence (rescued by Ifnar1/STING/cGAS loss,
  as reviewed in PMID:29259162), so DNASE2 is not itself an erythropoiesis participant.
• Undigested DNA -> cGAS/STING type I IFN and TNF-driven polyarthritis
  PMID:17066036.
• Cell-autonomous lysosomal clearance of damaged nuclear DNA delivered by autophagy
  PMID:25284779; mtDNA escaping autophagy in
  DNase II-deficient cardiomyocytes triggers TLR9 inflammation PMID:22535248.
• Generates TLR9 ligands from CpG-A / bacterial DNA in endolysosomes of DCs
  PMID:25600358.
• Efferocytosis-induced macrophage proliferation (mouse BMDM and in vivo): DNase II
  hydrolyses apoptotic-cell DNA in the phagolysosome to oligonucleotides that drive
  DNA-PKcs -> mTORC2 (RICTOR) -> MYC signalling [PMID:34784501 "the phagolysosomal enzyme
  that digests AC-DNA into oligonucleotides"; "Silencing Dnase2a resulted in decreased EdU
  incorporation into AC+ macrophages"]. DNase II provides the signal (substrate
  conversion); it is not a signal transducer. Not annotated as a NEW process here.

Human disease

• Biallelic hypomorphic DNASE2 variants cause autoinflammatory-pancytopenia syndrome
  (type I interferonopathy) PMID:29259162; JAK inhibition used therapeutically
  [PMID:31775019, letter, no abstract in cache].

Evolution

• DNase II family is an ancient eukaryotic trait associated with phagotrophy
  PMID:18226927; C. elegans NUC-1 degrades
  apoptotic-cell DNA in the engulfing step PMID:10716942.

Curation decisions (summary)

• GO:0004531 deoxyribonuclease II activity: core MF (accept all rows).
• GO:0004520 DNA endonuclease activity: MODIFY -> GO:0004531.
• GO:0006259 DNA metabolic process: MODIFY -> GO:0006308.
• GO:0006309 apoptotic DNA fragmentation (IBA, worm seeds): kept non-core; in mammals
  DNase II acts in the engulfing cell, not in the CAD-mediated cell-autonomous step.
• protein binding (CANX, high-throughput): REMOVE per protein-binding policy.
• NEW: GO:0043202 lysosomal lumen (IC).