Affinage

Showing DCLRE1C — ARTEMIS is a alias.

DCLRE1C

Protein artemis · UniProt Q96SD1

Length
692 aa
Mass
78.4 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DCLRE1C encodes Artemis, a nuclear metallo-β-lactamase/β-CASP-superfamily nuclease that is the principal structure-specific endonuclease of non-homologous end joining (NHEJ) and V(D)J recombination (PMID:11955432, PMID:11336668, PMID:12055248). Purified Artemis intrinsically possesses 5'-to-3' single-stranded DNA exonuclease activity, but upon forming a stable, DNA-independent complex with DNA-PKcs it gains endonucleolytic activity at hairpins, 5' and 3' overhangs, loops, flaps, gaps, and other single-to-double-strand transitions (PMID:11955432, PMID:15936993). Both the exo- and endonuclease activities share a single active site within the metallo-β-lactamase domain, where mutagenesis of conserved histidine/aspartate residues (including H115) abolishes endonuclease and hairpin-opening function; a second β-CASP metal site unique to Artemis explains its predominantly endonucleolytic behavior (PMID:15071507, PMID:34387696, PMID:24500713). Activation is gated by DNA-PKcs autophosphorylation at the T2609–T2647 cluster, which relieves an autoinhibitory Artemis C-terminal tail rather than requiring direct Artemis phosphorylation; truncating this tail yields constitutive hairpin-opening activity, and Ku80 supports the relevant autophosphorylation (PMID:16874298, PMID:16093244, PMID:16914548, PMID:19103741). Within NHEJ, the Artemis C-terminus directly binds the DNA Ligase IV DNA-binding domain through an extended hydrophobic interface to coordinate end processing with ligation, while Artemis and XRCC4 occupy mutually exclusive sites on DNA-PKcs, enforcing sequential recruitment during repair (PMID:22529269, PMID:23219551, PMID:35801871, PMID:28696258). Loss of Artemis causes radiosensitive severe combined immunodeficiency (RS-SCID) through a failure to open RAG-generated coding hairpins, producing defective coding-joint formation while signal joints remain intact (PMID:11336668, PMID:12504013, PMID:12055248). Beyond canonical end joining, Artemis acts downstream of ATM with the MRN complex to repair a slow-repairing, heterochromatin-associated subset of radiation-induced double-strand breaks and to promote homologous recombination in G2, and is regulated by ATM/ATR phosphorylation at S516/S645 governing G2/M and S-phase checkpoint recovery via Cdk1–cyclin B and SCF-Fbw7/cyclin E control (PMID:15574327, PMID:19779458, PMID:17242184, PMID:15723659, PMID:19423708).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2001 High

    Establishing the gene's identity answered why a class of human SCID arose, linking an uncharacterized metallo-β-lactamase-family protein to V(D)J recombination and DSB repair.

    Evidence Positional cloning and sequence analysis of patient mutations causing RS-SCID

    PMID:11336668

    Open questions at the time
    • Did not define the biochemical activity of the protein
    • No mechanism for how mutations impair recombination
  2. 2002 High

    Reconstitution with purified components answered what Artemis does enzymatically and how it is switched on, defining the DNA-PKcs-dependent acquisition of endonuclease and hairpin-opening activity.

    Evidence In vitro reconstitution with purified Artemis and DNA-PKcs, endo/exonuclease assays, RAG-hairpin opening

    PMID:11955432

    Open questions at the time
    • Did not resolve which active site mediates each activity
    • Mechanism of DNA-PKcs activation of Artemis not defined
  3. 2002 High

    Knockout mice and patient complementation established the in vivo physiological requirement, showing Artemis loss specifically blocks coding-hairpin opening while sparing signal joints, and confers radiosensitivity and genomic instability.

    Evidence Artemis-null mice, V(D)J and radiation assays; complementation of SCIDA patient fibroblasts with nuclear localization

    PMID:12055248 PMID:12504013

    Open questions at the time
    • Did not address Artemis roles outside lymphoid development
    • Subcellular dynamics during repair not defined
  4. 2004 High

    Active-site mutagenesis answered which catalytic function is required for recombination, separating dispensable exonuclease from essential endonuclease/hairpin-opening activity.

    Evidence Mutagenesis of eight conserved His/Asp residues with in vitro nuclease and in vivo V(D)J assays

    PMID:15071507

    Open questions at the time
    • Did not determine whether exo and endo activities use one or two active sites
    • Structural basis unresolved
  5. 2004 High

    Epistasis analysis placed Artemis genetically downstream of ATM in repair of a defined minor DSB subset, distinguishing its repair role from checkpoint signaling.

    Evidence Epistasis, irradiation survival, ATM-dependent phosphorylation, nuclease-dead mutants

    PMID:15574327

    Open questions at the time
    • Did not identify the chromatin context of the ~10% slow-repair fraction
    • Did not define the repair pathway used
  6. 2004 Medium

    DNA-damage phosphorylation studies connected Artemis to checkpoint machinery, showing ATM/ATR phosphorylation and a requirement for normal G2/M arrest.

    Evidence Phosphorylation after IR/UV, co-IP with checkpoint proteins, G2/M assays; complementation with phospho-mutants

    PMID:15456891 PMID:15468306

    Open questions at the time
    • Phospho-mutants still complemented V(D)J/radiosensitivity, leaving checkpoint role functionally separable
    • Direct checkpoint effectors not identified
  7. 2005 High

    Phosphosite mapping clarified the regulatory logic, localizing DNA-PKcs phosphorylation to a C-terminal domain that exerts negative regulation relieved upon phosphorylation.

    Evidence Mass-spec phosphosite mapping, kinase and endonuclease assays with phospho-mutants

    PMID:16093244

    Open questions at the time
    • Did not show direct structural autoinhibition
    • Did not exclude phosphorylation-independent activation
  8. 2005 Medium

    Showing ATM/Nbs1-dependent hyperphosphorylation and MRN association integrated Artemis into the ATM-MRN DSB-response axis.

    Evidence Phosphorylation in ATM/Nbs1-null cells, complementation, co-IP with MRN

    PMID:15723659

    Open questions at the time
    • Functional consequence of MRN association not defined
    • Single-lab co-IP without structural detail
  9. 2006 High

    Mechanistic dissection of activation showed DNA-PKcs autophosphorylation (T2609-T2647 cluster), not Artemis phosphorylation per se, licenses endonuclease activity, and that C-terminal truncation relieves autoinhibition.

    Evidence DNA-PKcs autophosphorylation mutants, Artemis truncation mutants, in vitro nuclease, in vivo V(D)J

    PMID:16874298 PMID:16914548

    Open questions at the time
    • Atomic basis of autoinhibition unresolved at the time
    • Did not define DNA-PKcs conformational changes driving activation
  10. 2006 Medium

    Substrate-range and recruitment studies broadened the role to a general structure-specific endonuclease that is loaded and retained on damaged chromatin by DNA-PKcs.

    Evidence In vitro assays on loops/flaps/gaps; chromatin fractionation and co-IP with DNA-PK and XRCC4/LigIV; phospho-foci localization

    PMID:15936993 PMID:16600297 PMID:16857680

    Open questions at the time
    • Ordering of recruitment relative to other NHEJ factors incomplete
    • Endonuclease cleavage geometry not structurally defined
  11. 2006 Medium

    Showing strict DNA-PK/ATP/Ku dependence for processing 3'-phosphoglycolate termini explained Artemis hypersensitivity to radiomimetic agents that generate such ends.

    Evidence In vitro nuclease on phosphoglycolate substrates; survival assays with bleomycin/neocarzinostatin/X-rays

    PMID:17121861

    Open questions at the time
    • Did not quantify contribution relative to other end-cleaning enzymes
    • In vivo flux not measured
  12. 2007 Medium

    Identifying ATM phosphosites S516/S645 mechanistically linked Artemis to G2/M checkpoint recovery through control of Cdk1-cyclin B localization and activation.

    Evidence Site-directed mutagenesis, phospho-antibodies, Cdk1-cyclin B co-IP and localization, checkpoint recovery assays

    PMID:17242184

    Open questions at the time
    • Direct enzymatic basis of Cdk1-cyclin B regulation unclear
    • Single-lab findings
  13. 2007 Medium

    In vivo AAV ITR processing and class-switch recombination studies extended hairpin-opening and DSB-joining functions to additional biological substrates.

    Evidence rAAV genome analysis in deficient mice; IgH locus FISH in Artemis-/- B cells during CSR

    PMID:17686847 PMID:18316419

    Open questions at the time
    • Tissue-specificity determinants of ITR processing unexplained
    • CSR role overlaps with DNA-PKcs and is not Artemis-unique
  14. 2008 Medium

    Ku80 C-terminus and apoptotic-pathway studies refined the activation hierarchy and revealed an additional pro-apoptotic function downstream of DNA-PKcs.

    Evidence Ku80 C-terminal deletion cells with nuclease assays; DT40 knockouts in etoposide-induced apoptosis with chromatin fractionation

    PMID:18674614 PMID:19103741

    Open questions at the time
    • Nuclease substrate in apoptosis induction not defined
    • Single-lab/cell-system specific
  15. 2009 High

    Demonstrating Artemis/ATM requirement for HR in G2 redefined Artemis as a phase-specific repair factor that channels heterochromatin-associated DSBs into homologous recombination.

    Evidence Epistasis with Brca2/Rad51/Rad54, ssDNA and Rad51 foci, nuclease-dead mutant, KAP-1 depletion

    PMID:19779458

    Open questions at the time
    • Precise endonucleolytic step initiating resection not defined
    • How phase determines NHEJ-vs-HR choice unresolved
  16. 2009 Medium

    Discovery of Fbw7 binding and p53 regulation expanded Artemis into cell-cycle/checkpoint control during replication and oxidative stress.

    Evidence Co-IP with Fbw7, cyclin E degradation and phospho-mutant analyses; siRNA epistasis showing DNA-PKcs-dependent p53 stabilization

    PMID:19398950 PMID:19423708

    Open questions at the time
    • Mechanistic link between nuclease function and ubiquitin-ligase regulation unclear
    • Single-lab co-IP partners
  17. 2011 Medium

    Identifying the Cul4A-DDB1-DDB2 interaction tied Artemis to p27 degradation and G1 progression, a function apparently distinct from its DSB nuclease activity.

    Evidence Co-IP with DDB2 and p27, siRNA knockdown, p27 degradation and cell-cycle assays

    PMID:22134138

    Open questions at the time
    • Whether nuclease activity is required is unknown
    • Single Co-IP-based partner identification
  18. 2012 High

    Mapping a direct Artemis C-terminus–Ligase IV interaction, later resolved structurally, showed how end processing is physically coupled to ligation during coding-joint formation.

    Evidence Co-IP/pulldown, point mutagenesis with V(D)J assays; X-ray crystallography of LigIV-DBD–Artemis peptide complex

    PMID:22529269 PMID:23219551

    Open questions at the time
    • Did not capture the full Artemis-LigIV assembly on DNA
    • Temporal coordination with DNA-PKcs release unresolved
  19. 2014 Medium

    Defining Artemis as a PTIP-binding 53BP1-pathway effector clarified how it suppresses end resection and competes with HR, with therapeutic relevance in BRCA1-deficient cells.

    Evidence Co-IP with PTIP, genetic epistasis with PARP-inhibitor resistance in BRCA1-deficient cells

    PMID:25512557

    Open questions at the time
    • Mechanism by which Artemis blocks resection not defined
    • Reconciliation with Artemis pro-HR role in G2 incomplete
  20. 2014 High

    Active-site analysis settled the long-standing question of activity origin, proving the 5'-exonuclease and endonuclease are intrinsic to Artemis and share one active site.

    Evidence Co-purification, H115A mutagenesis, cation dependence, parallel inhibitor sensitivity

    PMID:20117966 PMID:24500713

    Open questions at the time
    • Structural basis for activity switching not yet defined here
    • Substrate-selection determinants unresolved
  21. 2017 Medium

    Showing X4-LIV can stimulate Artemis at 3' overhangs independently of DNA-PKcs revealed alternative, sequential activation routes during NHEJ.

    Evidence In vitro reconstitution with defined substrates varying NHEJ components

    PMID:28696258

    Open questions at the time
    • In vivo relevance of DNA-PKcs-independent activation unclear
    • Order of factor handoff not directly visualized
  22. 2018 Medium

    Recruitment to stalled replication forks established a replication-stress role, with Artemis cleaving forks to promote restart and prevent mitotic mis-segregation.

    Evidence siRNA knockdown, chromatin fractionation, DNA fiber and mitotic segregation assays; non-epistatic with XPF-ERCC1

    PMID:30059501

    Open questions at the time
    • Exact fork substrate cleaved by Artemis not defined
    • Regulation distinct from NHEJ recruitment unclear
  23. 2021 High

    Crystal structures of the Artemis catalytic domain explained its endonuclease bias via a unique second metal site and showed the isolated domain is catalytically self-sufficient, enabling inhibitor development.

    Evidence X-ray crystallography of wildtype and variant catalytic domain, endonuclease assays, ebselen inhibition

    PMID:34387696

    Open questions at the time
    • Did not show full-length autoinhibited architecture
    • Substrate-bound catalytic state not captured
  24. 2022 High

    Cryo-EM of the basal Artemis:DNA-PKcs complex visualized the pre-activation architecture and revealed mutually exclusive Artemis/XRCC4 binding on DNA-PKcs, explaining ordered NHEJ assembly.

    Evidence Cryo-EM of basal complex, XRCC4 peptide competition assays

    PMID:35801871

    Open questions at the time
    • Activated (post-autophosphorylation) state not resolved
    • DNA-engaged cleavage-competent conformation undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single nuclease is allosterically switched between exo- and endonucleolytic modes and how its many regulatory partners (DNA-PKcs, LigIV, PTIP, Fbw7, DDB2, MRN) are temporally coordinated to dictate NHEJ-versus-HR pathway choice across cell-cycle phases.
  • No structure of the activated DNA-bound cleavage complex
  • Mechanism integrating repair and checkpoint/ubiquitin-ligase functions unknown
  • How resection-suppression and pro-HR roles are reconciled is unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 5 GO:0003677 DNA binding 3 GO:0016787 hydrolase activity 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 3
Partners
CDKN1BDDB2FBXW7LIG4PAXIP1PRKDCXRCC4XRCC6
Complex memberships
Artemis:DNA-PKcs complexDNA-PK (Ku/DNA-PKcs/Artemis) chromatin complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Artemis forms a stable complex with DNA-PKcs in the absence of DNA. Purified Artemis alone possesses 5' to 3' single-strand-specific exonuclease activity. Upon complex formation, DNA-PKcs phosphorylates Artemis, and Artemis acquires endonucleolytic activity on 5' and 3' overhangs as well as hairpins. The Artemis:DNA-PKcs complex can open hairpins generated by the RAG complex. In vitro reconstitution, purified protein biochemical assays, endonuclease/exonuclease activity assays Cell High 11955432
2001 Artemis is a novel protein whose mutations cause human RS-SCID. Protein sequence analysis identifies Artemis as a member of the metallo-beta-lactamase superfamily, involved in V(D)J recombination and DNA double-strand break repair. Positional cloning, protein sequence analysis, genetic mutation identification in patients Cell High 11336668
2004 ATM and Artemis function in a common DSB repair pathway (epistasis analysis). Radiation-induced Artemis hyperphosphorylation is ATM-dependent. The DSB repair process requires Artemis nuclease activity and rejoins approximately 10% of radiation-induced DSBs. Artemis is a downstream component of the ATM signaling pathway required for DSB repair but dispensable for ATM-dependent cell cycle checkpoint arrest. Epistasis analysis, irradiation survival assays, phosphorylation analysis, nuclease-dead mutants Molecular cell High 15574327
2006 DNA-PKcs autophosphorylation at the T2609-T2647 cluster (in the presence of Ku and target DNA) is required for Artemis-mediated endonuclease activity. Autophosphorylated DNA-PKcs stably associates with Ku-bound DNA with large single-stranded overhangs until overhang cleavage by Artemis. Artemis phosphorylation per se (at S503, S516, S645) is dispensable for endonuclease activity in vitro and for DSB repair and V(D)J recombination in vivo. In vitro endonuclease assays with autophosphorylation mutants of DNA-PKcs, cell-based V(D)J recombination assays, phospho-specific antibodies The EMBO journal High 16874298
2004 Active-site mutagenesis of eight conserved histidine and aspartate residues within the metallo-beta-lactamase domain of Artemis abolishes both hairpin-opening and overhang endonucleolytic activities but does not impair 5' to 3' exonuclease activity, indicating that hairpin-opening/endonuclease activity is necessary for V(D)J recombination while exonuclease activity is not sufficient. Site-directed mutagenesis of catalytic residues, in vitro biochemical nuclease assays, in vivo V(D)J recombination assay The EMBO journal High 15071507
2005 All DNA-PKcs phosphorylation sites on Artemis (11 sites) and three basal phosphorylation sites are located in the C-terminal domain. Phosphatase-treated Artemis and Artemis mutated at basal phosphorylation sites retain DNA-PKcs-dependent endonucleolytic activities. The C-terminal domain may have a negative regulatory effect on Artemis endonucleolytic activities, and phosphorylation by DNA-PKcs in the C-terminal domain may relieve this inhibition. Mass spectrometry phosphosite mapping, in vitro kinase assays, endonuclease activity assays with phosphorylation mutants The Journal of biological chemistry High 16093244
2006 The Artemis:DNA-PKcs complex cleaves DNA loops, flaps, and gaps — all substrates containing single-to-double-strand transitions — near the transition region. This versatile structure-specific endonuclease activity depends on complex formation and is important for NHEJ of incompatible DNA ends. In vitro endonuclease assays with defined DNA substrates (heterologous loops, stem-loops, flaps, gapped substrates) DNA repair High 15936993
2006 A region of the Artemis C-terminal tail mediates interaction with DNA-PKcs. C-terminally truncated Artemis variants exhibit intrinsic hairpin-opening activity without DNA-PKcs activation, indicating that autoinhibition by the C-terminal tail is relieved by DNA-PKcs phosphorylation. DNA-PKcs may also optimally configure 5' and 3' overhang substrates for Artemis endonucleolytic function. C-terminal truncation mutant analysis, in vitro nuclease assays, co-immunoprecipitation The Journal of biological chemistry High 16914548
2009 In G2 phase, Artemis (requiring its endonuclease activity) and ATM are required for homologous recombination repair of approximately 15% of radiation-induced DSBs, promoting single-stranded DNA and Rad51 foci formation. ATM and Artemis promote NHEJ in G1 but HR in G2, and this HR in G2 repairs heterochromatin-associated DSBs (dependency relieved by KAP-1 depletion). Epistasis analysis with siRNA knockdown of Artemis, Brca2, Rad51, Rad54; gamma-H2AX and Rad51 foci analysis; nuclease-dead Artemis mutant The EMBO journal High 19779458
2002 Artemis-deficient mice display severe combined immunodeficiency with defects in opening and joining V(D)J coding hairpin ends and increased ionizing radiation sensitivity, phenocopying DNA-PKcs-deficient mice. Artemis deficiency leads to chromosomal instability in fibroblasts. Signal joint formation is intact while coding joint formation is impaired, consistent with a hairpin coding end opening defect. Artemis knockout mouse model, V(D)J recombination assays, radiation sensitivity assays, chromosomal stability analysis Molecular cell High 12504013
2002 The SCIDA (Athabascan SCID) gene is identified as Artemis (SNM1-like). A founder nonsense mutation truncates the protein in 21 SCIDA patients. Wild-type Artemis complements defective coding joint and reduced signal joint formation in SCIDA fibroblasts. Artemis encodes a nuclear protein. Positional cloning, complementation assay in patient fibroblasts, subcellular localization by immunostaining Journal of immunology High 12055248
2006 Artemis is mobilized to damaged chromatin together with DNA-PK and XRCC4/ligase IV upon DSB induction. DNA-PKcs is necessary for loading of Artemis on damaged DNA. DNA-PKcs kinase activity maintains Artemis association with the DNA-PK:DNA complex, while Ku mediates assembly of DNA-PK on DNA ends and is responsible for dissociation of the DNA-PKcs:Artemis complex under kinase-preventive conditions. Cell fractionation/chromatin immunoprecipitation, co-immunoprecipitation in nuclear extracts, in vitro DNA-binding assays with kinase inhibitors The Journal of biological chemistry Medium 16857680
2004 Artemis is phosphorylated by ATM or ATR following ionizing radiation or UV irradiation, respectively. Artemis interacts with known cell cycle checkpoint proteins. Artemis is required for the maintenance of normal DNA damage-induced G2/M cell cycle arrest. Phosphorylation analysis after DNA damage, co-immunoprecipitation with checkpoint proteins, G2/M checkpoint assay in Artemis-depleted cells Molecular and cellular biology Medium 15456891
2007 ATM phosphorylates Artemis at S516 and S645 in response to ionizing radiation. Mutation of S516 and S645 results in defective recovery from the G2/M checkpoint. Mutant Artemis promotes enhanced interaction between unphosphorylated cyclin B and Cdk1, causing inhibitory Wee1-mediated phosphorylation of Cdk1, and causes retention of Cdk1-cyclin B in the centrosome with inhibition of nuclear import during prophase. Site-directed mutagenesis, phospho-specific antibodies, co-immunoprecipitation, immunofluorescence localization of Cdk1-cyclin B, G2/M checkpoint recovery assay Molecular and cellular biology Medium 17242184
2014 Artemis is a PTIP-binding protein (identified by co-immunoprecipitation). Loss of Artemis restores PARP-inhibitor resistance in BRCA1-deficient cells, placing Artemis as the major downstream effector of the 53BP1 pathway, which prevents end resection and promotes NHEJ in competition with homologous recombination. Co-immunoprecipitation, genetic epistasis (Artemis loss-of-function in BRCA1-deficient cells), cell survival assays with PARP inhibitors Genes & development Medium 25512557
2012 The Artemis C-terminal region directly interacts with the DNA-binding domain of DNA Ligase IV. This interaction is specific and independent of DNA and DNA-PKcs. Point mutations in Artemis disrupting Ligase IV or DNA-PKcs interactions reduce V(D)J recombination coding joint formation, with additive effects when both interactions are disrupted. Signal joint formation is unaffected. Co-immunoprecipitation, pulldown assays, point mutagenesis, V(D)J recombination assay The Journal of experimental medicine High 22529269
2012 Crystal structure of the DNA Ligase IV DNA-binding domain in complex with a peptide from the Artemis C-terminal region reveals that LigIV interacts with Artemis through an extended hydrophobic surface. Helix α2 in LigIV-DBD is longer than in other mammalian ligases and presents residues specifically interacting with Artemis. Mutations of key LigIV-DBD hydrophobic surface residues abolish the interaction. X-ray crystallography of LigIV-DBD apo and Artemis peptide complex, mutagenesis confirming interface Cell reports High 23219551
2022 Cryo-EM structures of the basal (pre-activated) state Artemis:DNA-PKcs complex show the Artemis catalytic domain dynamically positioned externally to DNA-PKcs prior to ABCDE autophosphorylation. Both catalytic and regulatory domains of Artemis interact with N-HEAT and FAT domains of DNA-PKcs. A mutually exclusive binding site exists for Artemis and XRCC4 on DNA-PKcs; an XRCC4 peptide disrupts the Artemis:DNA-PKcs complex. Cryo-EM structural analysis, agarose-acrylamide gel system for complex stabilization, XRCC4 peptide competition assay Nucleic acids research High 35801871
2021 Crystal structures of the catalytic domain of wildtype and variant Artemis reveal a second metal binding site in the β-CASP domain unique to Artemis (absent in SNM1A/SNM1B), explaining predominantly endonucleolytic activity. The catalytic domain alone has similar endonuclease activity to phosphorylated full-length protein. An RS-SCID Omenn syndrome variant is structurally characterized. Ebselen can inhibit the second metal binding site. X-ray crystallography of Artemis catalytic domain (wildtype and variants), in vitro endonuclease activity assays, small molecule inhibitor testing Nucleic acids research High 34387696
2006 Processing of 3'-phosphoglycolate-terminated DNA double-strand break termini by Artemis nuclease is completely dependent on DNA-dependent protein kinase and ATP, and is largely dependent on Ku. Artemis efficiently removes terminal nucleotides from phosphoglycolate-terminated 3' overhangs in a manner distinct from hydroxyl-terminated substrates. Human cells lacking Artemis are hypersensitive to bleomycin, neocarzinostatin, and X-rays, which all induce 3'-phosphoglycolate-terminated DSBs. In vitro Artemis nuclease assays with 3'-phosphoglycolate substrates, cell survival assays with DNA-damaging agents in Artemis-deficient cells The Journal of biological chemistry Medium 17121861
2010 Purified Artemis exhibits single-stranded DNA endonuclease activity that is stimulated by DNA-PKcs. The divalent cation dependence and sequence dependence of this single-stranded endonuclease activity parallels the double-stranded DNA endonuclease activity of Artemis:DNA-PKcs. In vitro endonuclease assays with purified Artemis and ssDNA substrates, modulation by antibodies and DNA-PKcs DNA repair Medium 20117966
2014 The 5'-exonuclease and endonuclease activities of Artemis co-purify and share the same active site: the H115A point mutant markedly reduces both activities, divalent cation effects on both activities parallel one another, and small molecule inhibitors block both activities in parallel. The 5'-exonuclease is intrinsic to Artemis. Co-purification analysis, active-site mutagenesis (H115A), divalent cation dependence assays, small molecule inhibitor studies The Journal of biological chemistry High 24500713
2015 Artemis resects iteratively into blunt DNA ends with efficiency reflecting AT-richness (DNA end breathing requirement). GC-rich blunt ends are not cut by Artemis alone. All blunt DNA ends are cut when DNA-PKcs and Ku accompany Artemis, but not when Ku is omitted — demonstrating Ku dependence of Artemis action on blunt DNA ends. In vitro nuclease assays with blunt and fixed pseudo-Y DNA structures, systematic variation of Ku presence/absence The Journal of biological chemistry Medium 26276388
2008 The Ku80 carboxy terminus supports DNA-PKcs autophosphorylation at Thr2647 (but not Ser2056), which in turn is required for Artemis nuclease activity in vivo and in vitro. Cells with Ku80 C-terminal deletion show severely reduced Artemis endonuclease activity. Ku80 carboxy-terminal deletion cell lines, phospho-specific antibodies, in vitro and in vivo Artemis nuclease activity assays, IR sensitivity Molecular and cellular biology Medium 19103741
2008 A DNA-PKcs missense mutation (L3062R) in an RS-SCID patient does not affect kinase activity or DNA end-binding capacity per se, but causes insufficient Artemis activation dependent on interaction with autophosphorylated DNA-PKcs, resulting in long P-nucleotide stretches in immunoglobulin coding joints. Patient mutation identification, heterologous expression system functional assay, immunoglobulin junction analysis The Journal of clinical investigation Medium 19075392
2006 Artemis phosphorylated by DNA-PKcs at S516 and S645 is concentrated in chromatin-associated nuclear foci in naïve cells. Phosphorylation at both sites in vivo shows dependence on DNA-PKcs association and is additionally stimulated by double-stranded DNA damage. The interface on Artemis required for DNA-PKcs association was delimited. Phospho-specific antibody immunofluorescence, chromatin fractionation, co-immunoprecipitation, V(D)J recombination assay with stable substrates Journal of molecular biology Medium 16600297
2004 Artemis is constitutively phosphorylated in cultured cells and undergoes additional IR-induced phosphorylation that is mainly but not solely ATM-dependent. In vitro-generated Artemis mutants with impaired IR-induced phosphorylation still display activity sufficient to complement V(D)J recombination defects and radiosensitivity of Artemis-deficient cells. Phosphorylation analysis, ATM-deficient cell lines, complementation assay in Artemis-deficient cells, V(D)J recombination assay European journal of immunology Medium 15468306
2005 Artemis is hyperphosphorylated in an ATM- and Nbs1-dependent manner in response to ionizing radiation, with S645 being a contributing SQ/TQ site. Reintroduction of wild-type ATM or Nbs1 reconstituted Artemis hyperphosphorylation in deficient cells. Hyperphosphorylated Artemis physically associates with the Mre11/Rad50/Nbs1 complex in an ATM-dependent manner in response to IR-induced DSBs. Phosphorylation analysis in ATM/Nbs1 null cells, complementation with wild-type ATM/Nbs1, co-immunoprecipitation of Artemis with MRN complex Cancer science Medium 15723659
2011 Artemis interacts with the Cul4A-DDB1 E3 ubiquitin ligase via direct interaction with substrate-specificity receptor DDB2. Artemis also interacts with CDK inhibitor p27. Both DDB2 and Artemis are required for degradation of p27 mediated by this complex. Regulation of p27 by Artemis and DDB2 controls cell cycle progression in normally proliferating cells and in response to serum deprivation. Co-immunoprecipitation, siRNA knockdown of Artemis and DDB2, p27 degradation assays, cell cycle analysis Cell cycle Medium 22134138
2009 Artemis interacts with the F-box protein Fbw7. This interaction, regulated by ATR-mediated phosphorylation at Ser516 and Ser645 in response to replication stress, promotes ubiquitylation and degradation of cyclin E through the SCFFbw7 E3 ubiquitin ligase complex. Mutation of Ser516/Ser645 causes prolonged S phase checkpoint recovery coinciding with stabilization of cyclin E and downregulation of Cdk2 kinase activity. Co-immunoprecipitation (Artemis-Fbw7), cyclin E degradation assays, phospho-mutant analysis, cell cycle recovery assays after UV/aphidicolin/hydroxyurea The Journal of biological chemistry Medium 19423708
2009 Artemis is a negative regulator of p53 in response to oxidative stress generated by mitochondrial respiration. Depletion of Artemis leads to spontaneous DNA-PKcs-dependent phosphorylation and stabilization of p53, resulting in G1 arrest and apoptosis. Co-depletion of DNA-PKcs (but not ATM) suppresses these effects. siRNA knockdown of Artemis and DNA-PKcs, p53 phosphorylation/stabilization assays, cell cycle analysis, antioxidant and mitochondrial inhibitor treatments Oncogene Medium 19398950
2008 DNA-PKcs and Artemis are required for joining a subset of AID-dependent DSBs during immunoglobulin class switch recombination. In the absence of either factor, B cells activated for CSR frequently generate AID-dependent IgH locus chromosomal breaks and translocations. IgH locus-specific FISH assay in DNA-PKcs-/- and Artemis-/- B cells activated for CSR, chromosomal break/translocation analysis The Journal of experimental medicine Medium 18316419
2007 DNA-PKcs and Artemis open AAV inverted terminal repeat (ITR) hairpin loops in a tissue-dependent manner in vivo. In the absence of either factor, ITR hairpin opening is impaired and double-stranded linear rAAV genomes with covalently closed hairpin termini accumulate. The 5' end of 3-base hairpin loops of the ITR is the primary target for DNA-PKcs- and Artemis-mediated cleavage. Recombinant AAV infection of DNA-PKcs- and Artemis-deficient mice, Southern blot analysis of rAAV genome metabolism in multiple tissues Journal of virology Medium 17686847
2017 XRCC4-DNA ligase IV (X4-LIV) stimulates Artemis nuclease activity on 3' overhangs in a DNA-PKcs-independent manner. X4-LIV cannot stimulate Artemis at hairpins or 5' overhangs. X4-LIV and DNA-PKcs interfere with each other with respect to stimulating Artemis at 3' overhangs, consistent with sequential rather than concurrent recruitment. In vitro nuclease assays and ligation assays with defined DNA substrate configurations, systematic variation of NHEJ protein components The Journal of biological chemistry Medium 28696258
2018 Artemis endonuclease (along with XPF-ERCC1) cleaves stalled DNA replication forks during S and G2 phases in response to replication stress, through non-epistatic pathways. Both nucleases are recruited to chromatin to promote replication fork restart. Artemis- and XPF-mediated rapid replication fork breakage prevents mitotic segregation defects. siRNA knockdown of Artemis and XPF-ERCC1, chromatin fractionation, DNA fiber assays, mitotic segregation analysis PLoS genetics Medium 30059501
2008 KU70, DNA-PKcs, and Artemis are essential for the rapid induction of apoptosis after massive DSB formation by high-dose etoposide. KU70 acts upstream of DNA-PKcs and Artemis acts downstream of DNA-PKcs in this apoptotic pathway. KU70 is required for chromatin binding of DNA-PKcs while Artemis is not required for DNA-PKcs chromatin binding, placing Artemis downstream of DNA-PKcs in apoptosis induction. Gene-targeted knockout DT40 cells, etoposide-induced apoptosis assay, caspase inhibitor studies, chromatin fractionation of DNA-PKcs in presence/absence of Artemis Cellular signalling Medium 18674614

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Artemis: sequence visualization and annotation. Bioinformatics (Oxford, England) 2524 11120685
2005 ACT: the Artemis Comparison Tool. Bioinformatics (Oxford, England) 1317 15976072
2002 Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 839 11955432
2004 A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Molecular cell 705 15574327
2001 Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 679 11336668
1991 Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. The Journal of experimental medicine 552 1711560
2008 Artemis and ACT: viewing, annotating and comparing sequences stored in a relational database. Bioinformatics (Oxford, England) 493 18845581
2009 ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. The EMBO journal 439 19779458
2006 DNA-PK autophosphorylation facilitates Artemis endonuclease activity. The EMBO journal 252 16874298
2008 A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. The Journal of clinical investigation 212 19075392
2002 Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Molecular cell 211 12504013
1994 Antisense oligonucleotides suppress B-cell lymphoma growth in a SCID-hu mouse model. Oncogene 180 8084613
2006 Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Current biology : CB 160 16730176
2005 Omenn syndrome due to ARTEMIS mutations. Blood 156 15731174
2003 Defective DNA repair and increased genomic instability in Artemis-deficient murine cells. The Journal of experimental medicine 154 12615897
2013 SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood 139 24144642
2006 Complete correction of murine Artemis immunodeficiency by lentiviral vector-mediated gene transfer. Proceedings of the National Academy of Sciences of the United States of America 139 17062750
2005 The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA repair 135 15936993
2002 A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans. Journal of immunology (Baltimore, Md. : 1950) 130 12055248
2020 Efficacy and safety of oral immunotherapy with AR101 in European children with a peanut allergy (ARTEMIS): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial. The Lancet. Child & adolescent health 126 32702315
2009 Efficient targeting of a SCID gene by an engineered single-chain homing endonuclease. Nucleic acids research 121 19584299
2003 Viewing and annotating sequence data with Artemis. Briefings in bioinformatics 121 12846394
2013 PRKDC mutations in a SCID patient with profound neurological abnormalities. The Journal of clinical investigation 120 23722905
2005 The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis. The Journal of biological chemistry 117 16093244
2004 Functional and biochemical dissection of the structure-specific nuclease ARTEMIS. The EMBO journal 114 15071507
2011 Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair. Nucleic acids research 104 21596788
2020 Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1). Ophthalmology 102 32544560
2004 Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. Molecular and cellular biology 102 15456891
2002 Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model. The Journal of clinical investigation 98 11877475
2014 PTIP associates with Artemis to dictate DNA repair pathway choice. Genes & development 97 25512557
2006 DNA-PKcs dependence of Artemis endonucleolytic activity, differences between hairpins and 5' or 3' overhangs. The Journal of biological chemistry 94 16914548
2017 A Process of Resection-Dependent Nonhomologous End Joining Involving the Goddess Artemis. Trends in biochemical sciences 91 28739276
2000 Characterization of anti-CCR5 ribozyme-transduced CD34+ hematopoietic progenitor cells in vitro and in a SCID-hu mouse model in vivo. Molecular therapy : the journal of the American Society of Gene Therapy 89 10933940
2004 Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proceedings of the National Academy of Sciences of the United States of America 87 14983023
2005 Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. DNA repair 83 15811628
2004 Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review. Genetics in medicine : official journal of the American College of Medical Genetics 81 14726805
2002 Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow. Blood 81 12406895
2015 DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Human molecular genetics 79 26476407
2006 Processing of 3'-phosphoglycolate-terminated DNA double strand breaks by Artemis nuclease. The Journal of biological chemistry 79 17121861
2005 Artemis links ATM to double strand break rejoining. Cell cycle (Georgetown, Tex.) 73 15684609
2008 DNA-PKcs and Artemis function in the end-joining phase of immunoglobulin heavy chain class switch recombination. The Journal of experimental medicine 72 18316419
2006 Interplay between Ku, Artemis, and the DNA-dependent protein kinase catalytic subunit at DNA ends. The Journal of biological chemistry 71 16857680
2015 Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency. The Journal of allergy and clinical immunology 65 25917813
2008 Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. American journal of human genetics 63 18252213
2021 Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2). Drugs 60 34724172
2016 Structure-Specific nuclease activities of Artemis and the Artemis: DNA-PKcs complex. Nucleic acids research 59 27198222
2022 Lentiviral Gene Therapy for Artemis-Deficient SCID. The New England journal of medicine 58 36546626
2008 The Ku80 carboxy terminus stimulates joining and artemis-mediated processing of DNA ends. Molecular and cellular biology 56 19103741
2007 The role of DNA-PKcs and artemis in opening viral DNA hairpin termini in various tissues in mice. Journal of virology 56 17686847
2000 Characterization of lymphocyte-dependent angiogenesis using a SCID mouse: human skin model of psoriasis. The journal of investigative dermatology. Symposium proceedings 55 11147678
2019 Baricitinib reverses HIV-associated neurocognitive disorders in a SCID mouse model and reservoir seeding in vitro. Journal of neuroinflammation 54 31561750
2017 Type I IFN-related NETosis in ataxia telangiectasia and Artemis deficiency. The Journal of allergy and clinical immunology 54 29155101
2012 Artemis C-terminal region facilitates V(D)J recombination through its interactions with DNA Ligase IV and DNA-PKcs. The Journal of experimental medicine 54 22529269
2006 Artemis phosphorylated by DNA-dependent protein kinase associates preferentially with discrete regions of chromatin. Journal of molecular biology 54 16600297
2004 Phosphorylation of Artemis following irradiation-induced DNA damage. European journal of immunology 53 15468306
2007 Artemis links ATM to G2/M checkpoint recovery via regulation of Cdk1-cyclin B. Molecular and cellular biology 51 17242184
2010 DNA-PKcs regulates a single-stranded DNA endonuclease activity of Artemis. DNA repair 50 20117966
2008 Stable and functional lymphoid reconstitution in artemis-deficient mice following lentiviral artemis gene transfer into hematopoietic stem cells. Molecular therapy : the journal of the American Society of Gene Therapy 50 18560421
2014 Evidence that the DNA endonuclease ARTEMIS also has intrinsic 5'-exonuclease activity. The Journal of biological chemistry 48 24500713
1995 Phosphorothioate oligonucleotides reduce melanoma growth in a SCID-hu mouse model by a nonantisense mechanism. Antisense research and development 46 8746776
2010 The most frequent DCLRE1C (ARTEMIS) mutations are based on homologous recombination events. Human mutation 45 19953608
2015 Unifying the DNA end-processing roles of the artemis nuclease: Ku-dependent artemis resection at blunt DNA ends. The Journal of biological chemistry 44 26276388
2013 The many faces of Artemis-deficient combined immunodeficiency - Two patients with DCLRE1C mutations and a systematic literature review of genotype-phenotype correlation. Clinical immunology (Orlando, Fla.) 44 24230999
2005 Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. Cancer science 43 15723659
2010 Molecular diagnosis of severe combined immunodeficiency--identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 mutations in a cohort of Chinese and Southeast Asian children. Journal of clinical immunology 42 21184155
2003 Novel Artemis gene mutations of radiosensitive severe combined immunodeficiency in Japanese families. Human genetics 42 12592555
2016 Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency. Human gene therapy 41 27611239
2008 KU70/80, DNA-PKcs, and Artemis are essential for the rapid induction of apoptosis after massive DSB formation. Cellular signalling 41 18674614
2012 Structural basis of DNA ligase IV-Artemis interaction in nonhomologous end-joining. Cell reports 39 23219551
2010 An Artemis polymorphic variant reduces Artemis activity and confers cellular radiosensitivity. DNA repair 39 20674517
2005 Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proceedings of the National Academy of Sciences of the United States of America 39 15699324
2015 Not All SCID Pigs Are Created Equally: Two Independent Mutations in the Artemis Gene Cause SCID in Pigs. Journal of immunology (Baltimore, Md. : 1950) 38 26320255
2007 Defective Artemis nuclease is characterized by coding joints with microhomology in long palindromic-nucleotide stretches. European journal of immunology 38 18034425
2001 In vivo suppression of Bcl-XL expression facilitates chemotherapy-induced leukaemia cell death in a SCID/NOD-Hu model. British journal of haematology 38 11260076
2018 Long-Term Health Outcome and Quality of Life Post-HSCT for IL7Rα-, Artemis-, RAG1- and RAG2-Deficient Severe Combined Immunodeficiency: a Single Center Report. Journal of clinical immunology 37 30105620
2002 The Greek Goddess, Artemis, reveals the secrets of her cleavage. DNA repair 37 12509281
2015 Characterization and evaluation of the artemis camera for fluorescence-guided cancer surgery. Molecular imaging and biology 36 25344146
2011 Virological characterization of patients failing darunavir/ritonavir or lopinavir/ritonavir treatment in the ARTEMIS study: 96-week analysis. Antiviral therapy 36 21311113
2007 Low-dose mistletoe lectin-I reduces melanoma growth and spread in a scid mouse xenograft model. British journal of cancer 36 18026191
2007 Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34+ cells isolated from Artemis or RAG1-deficient patients. Molecular therapy : the journal of the American Society of Gene Therapy 36 18223550
2008 The requirement of Artemis in double-strand break repair depends on the type of DNA damage. DNA and cell biology 35 17941805
2004 Artemis sheds new light on V(D)J recombination. Immunological reviews 35 15242402
2006 Radiation-induced delayed cell death in a hypomorphic Artemis cell line. Human molecular genetics 34 16540517
2005 The eukaryotic Pso2/Snm1/Artemis proteins and their function as genomic and cellular caretakers. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 34 15761611
2005 Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantation. Journal of immunology (Baltimore, Md. : 1950) 33 15699179
2005 Damaging-agent sensitivity of Artemis-deficient cell lines. European journal of immunology 32 15770702
2011 Artemis interacts with the Cul4A-DDB1DDB2 ubiquitin E3 ligase and regulates degradation of the CDK inhibitor p27. Cell cycle (Georgetown, Tex.) 31 22134138
2009 Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability. The Journal of experimental medicine 31 19349461
2021 Structural and mechanistic insights into the Artemis endonuclease and strategies for its inhibition. Nucleic acids research 30 34387696
2017 Effects of DNA end configuration on XRCC4-DNA ligase IV and its stimulation of Artemis activity. The Journal of biological chemistry 30 28696258
2010 Cytotoxicity associated with artemis overexpression after lentiviral vector-mediated gene transfer. Human gene therapy 29 20163250
2008 Expression of CD44 is associated with a metastatic pattern of human neuroblastoma cells in a SCID mouse xenograft model. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 18612220
2009 Artemis is a negative regulator of p53 in response to oxidative stress. Oncogene 28 19398950
2022 Structural analysis of the basal state of the Artemis:DNA-PKcs complex. Nucleic acids research 27 35801871
2018 DNA replication stress triggers rapid DNA replication fork breakage by Artemis and XPF. PLoS genetics 27 30059501
2011 Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide. Genes and immunity 27 21390052
2010 Purification and characterization of exonuclease-free Artemis: Implications for DNA-PK-dependent processing of DNA termini in NHEJ-catalyzed DSB repair. DNA repair 27 20347402
2010 A hypomorphic Artemis human disease allele causes aberrant chromosomal rearrangements and tumorigenesis. Human molecular genetics 27 21147755
2009 Artemis regulates cell cycle recovery from the S phase checkpoint by promoting degradation of cyclin E. The Journal of biological chemistry 27 19423708
1995 BCL-2 expression by leukaemic blasts in a SCID mouse model of biphenotypic leukaemia associated with the t(4;11)(q21;q23) translocation. British journal of haematology 27 7669664

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