DCLRE1C encodes Artemis, a metal-dependent DNA nuclease with an N-terminal metallo-β-lactamase/β-CASP region and a regulatory C-terminal region. Its central performed role is internal cleavage of exposed DNA regions, including coding-end hairpins and overhangs, before DNA ligase IV joins the processed ends. Purified human-protein experiments distinguish ssDNA endonucleolysis from terminal trimming, and human patient-derived chromosomal recombination assays link the catalytic region to coding-joint formation [PMID:20117966; PMID:14744996; PMID:11955432]. One integrated core joins this chemistry to NHEJ and V(D)J recombination. The new V(D)J assertion rests on a performed incision step plus direct cellular assays, rather than immune deficiency alone.
DNA-PKcs helps license Artemis end processing in a substrate-, salt- and Ku-dependent manner. DNA-PKcs autophosphorylation must be distinguished from phosphorylation of Artemis itself: the latter is not a universal obligatory catalytic switch. Historical Reactome summaries retain earlier phosphorylation language; the positive Artemis location and end-processing paths remain usable without adopting every mechanistic statement [PMID:16874298; PMID:20117966; Reactome:R-HSA-5693533]. Artemis is the nuclease; PRKDC is the protein kinase and LIG4 is the joining enzyme.
The weaker exonuclease activity has a substantive experimental history. Hydroxyapatite fractionation separated most exonuclease from Artemis in one study. A later study used WT/H115A, cofractionation, circular-dichroism, association, poly(dA), end-label and inhibition controls to support intrinsic nonprocessive ssDNA exonuclease. An independent full-length preparation also showed weak activity, whereas its engineered catalytic-domain construct did not. These results support retention of the measured biochemical capability, with physiological importance unresolved, rather than removal as an assumed contaminant or promotion to a second core [PMID:20347402; PMID:24500713; PMID:34387696]. The corresponding PAINT DNA-exonuclease assertion is a valid ancestor-node inference from experimentally characterized DCLRE1A; it is not a direct Artemis experiment PMID:22692201.
Artemis has distinct binding interfaces for LIG4 and PRKDC. Human cellular co-immunoprecipitation is complemented by direct LIG4-fragment binding, calorimetry and structures with the Artemis 485–495 peptide. These support enzyme-binding and protein-serine/threonine-kinase-binding refinements, without transferring the partners’ catalytic functions to Artemis. The peptide structures do not represent intact Artemis, and positive AP-MS association is not automatically a purified binary interaction [PMID:22529269; PMID:23219551; PMID:23523427; PMID:33961781]. The original nuclear DNA-PKcs purification also explicitly detects Artemis, despite the paper’s focus on XLS PMID:25941166.
The major functional setting is nucleoplasm and the NHEJ repair assembly. Tagged human Artemis was observed in nuclei outside nucleoli, and the HPA data record independently identifies supported nucleoplasmic localization. The data record, not its microscopy images, was inspected; its additional Golgi entry is preserved as context. The broad nucleus assertions remain true but less informative than the accepted nucleoplasm location [PMID:12055248; PMID:15071507; GO_REF:0000052].
Four official products are retained: 692, 572, 577 and 434 residues. Products 2 and 3 alter the N-terminal catalytic region; product 4 changes the tail after residue 385 and loses the remaining canonical C terminus. These sequence differences do not prove inactivity or equivalent activity. The 1–385 engineered construct that restores chromosomal recombination is not the natural 434-residue product, and its radiation-growth rescue differed from full length under conditions with lower protein abundance PMID:14744996. The cDNA papers support sequence provenance rather than interchangeable repair functions [PMID:14702039; PMID:15489334]. No product assignment is inserted into an imported source row that lacks it.
Telomere maintenance is a contextual contribution. Mouse Artemis evidence is present among the actual PAINT descendants, and human Artemis-defective fibroblasts display mild telomeric fusions and population-doubling-dependent TIF changes. Younger cells did not have the same TIF phenotype; no direct telomere-specific Artemis incision reaction was established [PMID:12615897; PMID:20678254].
Interstrand-cross-link repair remains unresolved for the human target despite a legitimate ancestral PAINT placement. Chicken DT40 Artemis loss did not increase the tested cisplatin/MMC sensitivity, while a single Artemis-null human HCT116 clone did. The human background is hMLH1-defective, and drug survival does not identify whether Artemis directly removes a cross-link or processes downstream DNA damage. Neither experiment establishes universal absence or a specific human cross-link incision mechanism [PMID:15572677; PMID:21785230]. The experimental contrast is retained explicitly rather than turning a valid inherited annotation into a wrong-paralog assertion.
For the external originals, PMID:15071507, PMC404326 contains the tagged-protein localization in the characterization Results/Figure 2 caption and indirect-immunofluorescence Methods. PMID:20678254, PMC2907561 contains the telomere results and immuno-FISH Methods. PMID:15572677, PMC533992 contains DT40 disruption, expression/colony Methods and differential-sensitivity Results. PMID:21785230, DOI 10.1269/jrr.10168 gives human Methods on printed pages 416–417, Results 418–420 and Discussion 421–422. These are selected actual text reads, not figure-pixel or whole-paper reading claims.
The chemistry sources are PMID:16874298, PMC1553186, PMID:20117966, PMC2847011, PMID:20347402, PMC2883643, PMID:24500713, PMC3953294 and PMID:34387696, PMC8450076. Their selected Methods/Results/captions were independently reviewed. The latter paper’s DNA-contact re-refinement has partial occupancy, crystallographic symmetry and disorder limits; longer extensions are modelled. Its Asp116 prose differs from the canonical Cys116 sequence, so no residue-specific metal-ligand geometry is asserted here.
The full original bodies for PMID:11955432 and PMID:12055248 were not recovered. Their positive abstracts are preserved and supplemented by independently read later evidence where appropriate. PMID:14702039 remains a publisher preview; PMID:15489334 was separately recovered as PMC528928. Normal publication-cache flags describe the immutable cache contents and do not erase separately recovered original access. Donor-paper abstracts and literal current GOA records were inspected as phylogenetic provenance; unexamined donor originals are not presented as direct human Artemis assays.
The source evidence guide provides exact lineage/IBD records, public interaction identifiers, assay scope and complete positive Reactome target paths. It is authored navigation, not an independent experimental reference. The Reactome traversal retained genuine HTTP 429 failures and does not claim to reconstruct the entire pathway. Default Falcon and configured perplexity-lite attempts genuinely failed; the manual research is not represented as provider output.
The supported LIG4 and PRKDC associations are refined by the demonstrated enzyme classes, without assigning either partner’s catalysis to Artemis. The ClinGen project instruction in main permits supported non-core generic binding when a narrower class is not established; uncertainty still requires source-specific assessment. Here all six existing generic-binding assertions have evidence-backed class refinements. The interstrand-cross-link assertion remains unresolved on the actual human and chicken experiments, independently of whether the paper bodies were accessible.
The three required changes in review 5556788610 and the suggested qualifier correction are applied without altering the 31 imported source assertions, four products, core or references.
The inherited GO:0035312 DNA-exonuclease assertion is now TOO_GENERAL: GO:0045145, already the supported MODIFY replacement on the GO:0008409 row, directly entails it through an is_a edge confirmed in QuickGO. This aligns the action with the existing substrate-specific evidence; it does not dispute the PAINT placement, the measured weak activity, or the unresolved physiological contribution.
GO:0003684 damaged DNA binding is retained as non-core because it is a broad inherited recognition descriptor distinct from the established catalytic end-processing core. The exact ancestral PAINT placement, experimentally grounded PSO2 source and separately inspected target structural contact remain valid evidence. The action change does not reject the inference based on donor count or lack of a direct assay in the donor paper.
For the PMID:33961781 PRKDC pair, the generic AP-MS methods supporting_text is removed while its reference identifier, class-specific refinement and complete literal-pair reason remain unchanged. The source guide already records the exact interaction accession, publication, host, bait feature and sequence-identity checks; the generic methods sentence was not pair-level evidence. No new quote or source-cache change is needed.
The existing NEW V(D)J recombination annotation receives qualifier involved_in. This records its intended process relation and does not create another annotation or change the participation evidence. Other optional suggestions are kept separate from these accepted corrections.