Affinage

CHEK2

Serine/threonine-protein kinase Chk2 · UniProt O96017

Round 2 corrected
Length
543 aa
Mass
60.9 kDa
Annotated
2026-04-28
130 papers in source corpus 46 papers cited in narrative 46 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHEK2 is a DNA damage-responsive serine/threonine kinase that integrates upstream signals from ATM, ATR, and DNA-PKcs to coordinate cell cycle checkpoints, apoptosis, DNA repair, and genome stability. ATM phosphorylates CHEK2 on Thr-68, triggering dimerization, autophosphorylation, and full kinase activation; CHEK2 then phosphorylates p53 (Ser-20), Cdc25A (Ser-123), Cdc25C (Ser-216), BRCA1 (Ser-988), MDMX (Ser-342/367), E2F-1, and HuR, thereby enforcing G1/S and intra-S checkpoints, promoting homologous recombination, stabilizing p53, and regulating mRNA stability (PMID:9836640, PMID:10710310, PMID:11298456, PMID:10724175, PMID:16511560, PMID:17317627). CHEK2 activity is negatively regulated by Wip1-mediated Thr-68 dephosphorylation, PIRH2-mediated polyubiquitylation, SIRT1-mediated deacetylation of Lys-520, and O-GlcNAcylation at Thr-378, and its nuclear import requires KPNA2 (PMID:16311512, PMID:23449389, PMID:31209362, PMID:33690219, PMID:12909615). Germline loss-of-function CHEK2 mutations cause Li-Fraumeni syndrome in families lacking TP53 mutations, and beyond canonical DNA damage signaling CHEK2 maintains chromosomal stability during mitosis via the CHEK2–BRCA1 pathway, eliminates defective oocytes through CHK2–p53/p63 signaling, and initiates senescence-associated inflammatory cytokine secretion (PMID:10617473, PMID:20364141, PMID:24482479, PMID:19597488).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    The initial question of whether a mammalian functional homolog of yeast checkpoint kinases Rad53/Cds1 exists was answered when CHEK2 was identified as an ATM-dependent kinase that phosphorylates Cdc25C on Ser-216, establishing the first link between ATM signaling and cell cycle regulation.

    Evidence In vitro kinase assay and immunoprecipitation of CHEK2 after IR in human cells

    PMID:9836640

    Open questions at the time
    • Upstream phosphorylation site on CHEK2 not yet mapped
    • In vivo relevance of Cdc25C Ser-216 phosphorylation not demonstrated
  2. 2000 High

    The mechanism of CHEK2 activation was resolved: ATM directly phosphorylates CHEK2 on Thr-68, which is required for full kinase activation and G1 arrest; simultaneously, CHEK2 was shown to phosphorylate p53 on Ser-20, disrupting MDM2 binding and stabilizing p53, and to phosphorylate BRCA1 on Ser-988, which is required for BRCA1-dependent DNA damage survival.

    Evidence In vitro kinase assays with Thr-68 mutagenesis, Chk2-/- mouse cells showing defective p53 stabilization, co-IP and co-localization of CHEK2–BRCA1 with Ser-988 mutagenesis and survival assays

    PMID:10673500 PMID:10710310 PMID:10724175 PMID:10973490 PMID:11025670

    Open questions at the time
    • Autophosphorylation sites beyond Thr-68 not characterized
    • Whether CHEK2 is the sole kinase for p53 Ser-20 in vivo unclear given Chk1 redundancy
  3. 2001 High

    Two key pathway connections were established: Nbs1 was placed between ATM and CHEK2 as a required mediator, and CHEK2-mediated Cdc25A Ser-123 phosphorylation was shown to enforce the intra-S-phase checkpoint by triggering Cdc25A degradation and preventing CDK2 activation.

    Evidence Complementation of NBS cells with wild-type versus S343A Nbs1 restoring CHEK2 activation; dominant-negative CHEK2 and tumor alleles blocking Cdc25A destruction and radioresistant DNA synthesis

    PMID:11298456 PMID:11438675

    Open questions at the time
    • Whether Nbs1 acts as a scaffold versus activator of ATM toward CHEK2 not resolved
    • Contribution of Chk1 to Cdc25A destruction not delineated
  4. 2002 High

    Chk2 knockout mice revealed that CHEK2 is specifically required for the G1/S checkpoint and p53-dependent transcription of p21 and Noxa after IR, while G2/M and S-phase checkpoints remain intact, clarifying checkpoint specificity; a p53-independent apoptotic pathway through PML was also identified.

    Evidence Chk2-/- mouse cell cycle and transcriptional analysis; dominant-negative CHEK2 in p53-null cells with PML co-IP

    PMID:12356735 PMID:12402044

    Open questions at the time
    • PML-mediated apoptosis pathway single-lab finding
    • Mechanism by which CHEK2 activates PML not detailed
  5. 2003 High

    CHEK2's substrate repertoire expanded beyond cell cycle regulators: it phosphorylates E2F-1 to stabilize it and promote DNA-damage-induced apoptosis, and KPNA2-mediated nuclear import via NLS-3 was defined as essential for CHEK2 function; substrate recognition was shown to involve a docking-site mechanism on p53.

    Evidence In vitro kinase assays on E2F-1 with dominant-negative CHEK2 blocking apoptosis; GST pulldown and GFP-localization of NLS-3 mutants; peptide-docking reconstitution for p53 phosphorylation

    PMID:12717439 PMID:12897801 PMID:12909615

    Open questions at the time
    • E2F-1 phosphorylation site identity not confirmed by mass spectrometry
    • In vivo relevance of NLS-3 not tested in animal models
  6. 2004 High

    CHEK2 was connected to replicative senescence at eroded telomeres and to regulation of homologous recombination: CHEK2-mediated BRCA1 Ser-988 phosphorylation specifically promotes HR over error-prone NHR, and CHEK2 activation at telomere-associated DNA damage foci drives p21-dependent senescence.

    Evidence HR/NHR reporter assays with S988A-BRCA1 and dominant-negative CHEK2; γ-H2AX co-localization at telomeres with CHEK2 inactivation extending lifespan

    PMID:14701743 PMID:15192702

    Open questions at the time
    • Whether BRCA1 Ser-988 phosphorylation affects other BRCA1 functions untested
    • Threshold model of CHEK2 autophosphorylation (Thr-387 requiring ≥19 DSBs) based on single lab
  7. 2005 High

    A negative feedback loop was identified: Wip1 phosphatase dephosphorylates CHEK2 Thr-68 to attenuate signaling, while CHEK2 phosphorylates MDMX at Ser-342/367 to promote its 14-3-3 binding, nuclear import, and MDM2-mediated degradation, thereby reinforcing p53 activation.

    Evidence In vitro phosphatase assay with recombinant Wip1, RNAi sustaining Thr-68 phosphorylation; MS-identified MDMX phosphosites with 14-3-3 binding and ubiquitination assays

    PMID:16163388 PMID:16311512 PMID:16511560

    Open questions at the time
    • Whether Wip1 targets other CHEK2 phosphosites unknown
    • Quantitative kinetics of MDMX degradation cycle not measured
  8. 2007 Medium

    CHEK2 was linked to post-transcriptional gene regulation: phosphorylation of the RNA-binding protein HuR at S100 causes release of SIRT1 mRNA, triggering its decay and reducing SIRT1 protein, establishing a CHEK2–HuR–SIRT1 axis; ATR was also shown to activate CHEK2 (rather than ATM) in response to cisplatin-induced replication stress.

    Evidence In vitro kinase assay on HuR with mutagenesis and RNA-IP showing mRNA dissociation; dominant-negative ATR/ATM and ATR-deficient fibroblasts with cisplatin

    PMID:17317627 PMID:18162465

    Open questions at the time
    • HuR phosphorylation sites predicted, not identified by MS
    • ATR-CHEK2 axis may be cell-type-specific (renal cells)
  9. 2009 Medium

    CHEK2 was shown to drive the senescence-associated secretory phenotype (SASP): persistent DNA damage signaling through ATM–NBS1–CHK2 initiates IL-6 secretion independently of p53 or pRb, revealing a non-cell-autonomous function of CHEK2 in tissue microenvironment remodeling.

    Evidence siRNA knockdown of CHK2 in senescent cells abolishing IL-6 secretion; oncogene-induced senescence model

    PMID:19597488

    Open questions at the time
    • Full spectrum of CHEK2-dependent secreted factors not characterized
    • Mechanism linking CHEK2 kinase activity to transcription of cytokine genes unknown
  10. 2010 High

    A DNA-damage-independent role was established: CHEK2 maintains chromosomal stability during mitosis by phosphorylating BRCA1, and its depletion causes abnormal spindle assembly, lagging chromosomes, and chromosomal instability, redefining CHEK2 as a constitutive mitotic kinase.

    Evidence siRNA depletion and kinase-dead CHEK2 expression with immunofluorescence of mitotic spindles, karyotyping, and live-cell imaging

    PMID:20364141

    Open questions at the time
    • Mitotic CHEK2 substrates beyond BRCA1 not identified
    • Whether CHEK2 mitotic function requires Thr-68 phosphorylation not resolved at this point
  11. 2013 High

    Negative regulation of CHEK2 protein levels was clarified: PIRH2 polyubiquitylates CHEK2 for proteasomal degradation in a phosphorylation-dependent manner, counteracted by the deubiquitylase USP28; Pirh2-/- cells accumulate CHEK2 and show enhanced checkpoint activation reversed by additional Chk2 deletion.

    Evidence Co-IP, ubiquitination assay, Pirh2-/- and Pirh2-/-Chk2-/- double-knockout epistasis with checkpoint assays

    PMID:23449389

    Open questions at the time
    • Whether PIRH2 ubiquitylation is constitutive or damage-regulated not fully resolved
    • Specific ubiquitin chain types on CHEK2 not determined
  12. 2014 High

    CHEK2's role in meiosis was established: CHK2 is essential for eliminating oocytes with unrepaired DSBs via p53 and the oocyte-specific TAp63 isoform, and ATR (not ATM) is the primary upstream kinase in oocytes; separately, DNA-PKcs was identified as the kinase phosphorylating CHEK2 Thr-68 during mitosis.

    Evidence Chk2-/- mouse crosses with meiotic recombination mutants rescuing female infertility; genetic epistasis with p53/p63 knockouts; DNA-PKcs depletion with phosphomimetic CHEK2 rescue in mitotic cells

    PMID:24482479 PMID:24492479

    Open questions at the time
    • Whether CHK2 has meiotic substrates beyond p53/p63 unknown
    • DNA-PKcs–CHEK2 mitotic axis not validated in non-cancer cell types
  13. 2019 High

    A new layer of CHEK2 regulation was uncovered: SIRT1 deacetylates CHEK2 at Lys-520, suppressing its phosphorylation, dimerization, and activation; Sirt1-/- neonatal lethality is rescued by Chk2 deletion, revealing that CHEK2 hyperactivation underlies SIRT1-loss phenotypes.

    Evidence Co-IP, deacetylation assay, dimerization assay, Sirt1-/-Chk2-/- double-knockout mouse rescue of neonatal lethality

    PMID:31209362

    Open questions at the time
    • Whether Lys-520 acetylation is constitutive or damage-induced not determined
    • Acetyltransferase responsible for Lys-520 acetylation not identified
  14. 2021 Medium

    CHEK2 was linked to metabolic regulation and post-translational modification by metabolites: O-GlcNAcylation of Thr-378 (driven by PCK1 loss and UDP-GlcNAc accumulation) impairs CHEK2 stability and dimerization to promote HCC proliferation, while CHEK2 itself regulates SDH expression and TCA cycle activity.

    Evidence MS-based O-GlcNAcylation mapping with T378 mutagenesis and PCK1-KO mouse model; NMR metabolomics with CHEK2 siRNA and SDH activity assay in transgenic HCC mice

    PMID:33690219 PMID:33762357

    Open questions at the time
    • O-GlcNAcylation–phosphorylation cross-talk at Thr-378 not biochemically resolved
    • Mechanism by which CHEK2 controls SDH transcription unknown
    • Metabolic roles validated only in HCC models

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full spectrum of mitotic CHEK2 substrates beyond BRCA1, the structural basis of CHEK2 activation by dimerization and autophosphorylation in cells, the identity of the acetyltransferase for Lys-520, and whether CHEK2's metabolic and mRNA-regulatory functions operate in normal physiology or are context-restricted.
  • No full-length CHEK2 activation structure in complex with upstream kinase
  • Mitotic substrate inventory incomplete
  • Metabolic and mRNA stability roles not validated outside cancer/stress models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 13 GO:0016740 transferase activity 6
Localization
GO:0005634 nucleus 4 GO:0005694 chromosome 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1640170 Cell Cycle 6 R-HSA-5357801 Programmed Cell Death 5 R-HSA-73894 DNA Repair 5 R-HSA-1643685 Disease 4 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ATMBRCA1CDC25AMDM4PIRH2PPM1DSIRT1TP53

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 CHEK2 (Chk2) was identified as the mammalian homolog of yeast Rad53/Cds1; it is rapidly phosphorylated and activated in response to DNA damage in an ATM-dependent manner and phosphorylates Cdc25C on serine-216 in vitro, linking ATM to cell cycle regulation. In vitro kinase assay, immunoprecipitation, ATM-dependent phosphorylation in cells Science High 9836640
1999 Human Cds1 (CHEK2) directly phosphorylates and inactivates Cdc25 phosphatase in vitro in response to DNA damage, providing a mechanism for inhibition of Cdc2/CDK2 and G2/M checkpoint enforcement. In vitro kinase/phosphatase assay, ionizing radiation treatment, wortmannin inhibition, ATM-dependence assay Current Biology High 9889122
1999 Heterozygous germline mutations in hCHEK2 occur in Li-Fraumeni syndrome families lacking TP53 mutations, establishing CHEK2 as a tumor suppressor gene that functions upstream of p53 in a G2 checkpoint pathway. Germline mutation analysis, functional cell-based assays Science High 10617473
2000 CHEK2 phosphorylates p53 directly on serine-20 in vitro and in vivo, preventing Mdm2 binding and thereby stabilizing p53 in response to DNA damage; Chk2-/- cells fail to stabilize p53 or induce p53-dependent transcripts after gamma-irradiation. Gene targeting (Chk2-/- mouse cells), in vitro kinase assay, p53 phosphorylation site mutagenesis, transcriptional reporter assay Science High 10710310
2000 ATM phosphorylates CHEK2 in vitro and in vivo predominantly on threonine-68 within the SQ/TQ cluster domain (SCD) in response to ionizing radiation; mutation of Thr68 to Ala reduces CHEK2 phosphorylation and activation after IR, and mutation of all seven SQ/TQ motifs abolishes IR-induced CHEK2 activation. In vitro kinase assay, site-directed mutagenesis, phospho-specific antibody, in vivo phosphorylation analysis PNAS High 10973490
2000 Threonine-68 of Cds1/CHEK2 is the preferred ATM phosphorylation site in vitro and the principal irradiation-induced phosphorylation site in vivo; a T68A mutant cannot be fully activated and fails to induce G1 arrest in response to ionizing radiation. In vitro kinase assay with ATM, in vivo phosphorylation mapping, dominant-negative and rescue experiments Nature Cell Biology High 11025670
2000 CHEK2 (Chk2/hCds1) stabilizes p53 by phosphorylating it on Ser-20, dissociating preformed p53-Mdm2 complexes; ectopic wild-type CHEK2 enhances p53 stabilization after DNA damage while dominant-negative CHEK2 abrogates both Ser-20 phosphorylation and p53 stabilization, resulting in G1 arrest. In vitro kinase assay, co-immunoprecipitation, ectopic expression/dominant-negative mutant, cell cycle profiling Genes & Development High 10673500
2000 hCds1/CHEK2 phosphorylates BRCA1 on serine-988; CHEK2 and BRCA1 interact and co-localize in discrete nuclear foci but separate after gamma irradiation, and Ser-988 phosphorylation is required for BRCA1 release from CHEK2 and for BRCA1-dependent survival after DNA damage. Co-immunoprecipitation, co-localization (immunofluorescence), in vitro kinase assay, site-directed mutagenesis, cell survival assay Nature High 10724175
2000 Human Chk1 and CHEK2 (hCds1) both phosphorylate tetrameric p53 at multiple DNA damage-inducible sites including Ser-20 in vitro; phosphorylation requires the tetrameric form of p53. In vitro kinase assay, biochemical fractionation, recombinant protein phosphorylation Genes & Development High 10673501
2001 IR-induced ATM-dependent activation of CHEK2 requires Nbs1; in NBS cells lacking Nbs1, CHEK2 phosphorylation and kinase activity toward Cdc25C are defective. Complementation with wild-type Nbs1 but not with an Nbs1-S343A mutant (ATM phosphorylation site) restores CHEK2 activation, placing Nbs1 between ATM and CHEK2 in the signaling cascade. Complementation assay in NBS cells, in vitro kinase assay, immunoprecipitation, phospho-specific western blot Molecular and Cellular Biology High 11438675
2001 ATM-Chk2 signaling pathway controls the S-phase checkpoint: CHEK2 phosphorylates Cdc25A on serine-123; IR-induced Cdc25A destruction requires both ATM and CHEK2-mediated Ser-123 phosphorylation, preventing CDK2 dephosphorylation and blocking DNA replication (radioresistant DNA synthesis). In vitro kinase assay, site-directed mutagenesis, epistasis with dominant-negative CHEK2 and tumor-associated CHEK2 alleles, flow cytometry for S-phase checkpoint Nature High 11298456
2002 Chk2-/- mice show impaired G1/S checkpoint but intact G2/M and S-phase checkpoints after ionizing radiation; IR-induced p53 stabilization is partial in Chk2-/- cells and p53-dependent transcriptional induction of p21 and Noxa is absent, demonstrating that CHEK2 regulates p53 transcriptional activity as well as stability. Chk2 knockout mouse generation, cell cycle checkpoint assays, qRT-PCR, western blot EMBO Journal High 12356735
2002 CHEK2 mediates gamma-irradiation-induced apoptosis through a p53-independent pathway involving PML (ATM-CHEK2-PML), establishing PML as a functional downstream effector of CHEK2 in the apoptotic response. Co-immunoprecipitation, dominant-negative CHEK2 expression, apoptosis assays in p53-null context Nature Cell Biology Medium 12402044
2003 CHEK2 phosphorylates and stabilizes E2F-1 in response to DNA damage; a CHEK2 consensus phosphorylation site in E2F-1 is phosphorylated upon etoposide treatment, increasing E2F-1 half-life, transcriptional activity, and localization to discrete nuclear structures; dominant-negative CHEK2 blocks E2F-1 induction and E2F-1-dependent apoptosis. In vitro kinase assay, dominant-negative CHEK2 expression, protein half-life assay, immunofluorescence localization, apoptosis assay Nature Cell Biology High 12717439
2003 CHK2 phosphorylates p53 at Thr-18 and Ser-20 via allosteric activation; two peptides from the p53 DNA-binding domain serve as CHK2-docking sites and activate CHK2 in trans toward BOX-I transactivation domain fragments, demonstrating a docking-site-based substrate recognition mechanism. In vitro kinase assay with peptide fragments, mutagenesis, biochemical docking assay EMBO Reports Medium 12897801
2003 Karyopherin-alpha2 (KPNA2) interacts with CHEK2 through NLS-3 (amino acids 515–522) and mediates its nuclear import; mutation of NLS-3 causes cytoplasmic relocalization of CHEK2, establishing the nuclear import mechanism. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, GFP-CHEK2 localization with NLS mutants Journal of Biological Chemistry Medium 12909615
2003 Tumor-associated CHEK2 mutations (R145W, I157T) in the FHA domain impair kinase activation: R145W cannot be phosphorylated at Thr-68 by ATM and cannot be activated after gamma radiation, forming an aberrantly large complex; wild-type CHEK2 exists in an ~200 kDa complex, whereas R145W forms a larger inactive complex. In vitro kinase assay, phosphorylation site analysis, gel filtration/complex size analysis, gamma-irradiation activation assay Journal of Biological Chemistry High 11053450
2003 Substrate specificity of CHEK2 kinase was determined: residues at positions -5 and -3 relative to the phosphorylation site are critical for substrate recognition, with consensus sequence defined; in vitro targets identified include Abl1, Bub1R, Bub1, Bub3, Plk1, Cdc25B, Mre11, and others. GST-peptide phosphorylation assay, mutational analysis of Cdc25A Ser-123 substrate Biochemical and Biophysical Research Communications Medium 12711320
2004 CHEK2-mediated phosphorylation of BRCA1 at Ser-988 regulates recombinational repair: prevention of Ser-988 phosphorylation disrupts BRCA1-dependent promotion of homologous recombination (HR) and suppression of error-prone nonhomologous recombination (NHR); dominant-negative CHEK2 yields the same phenotype. Site-directed mutagenesis of BRCA1 Ser-988, HR and NHR assays, dominant-negative CHEK2 Molecular and Cellular Biology High 14701743
2004 CHEK2 autophosphorylation on Thr-387 is triggered by ≥19 DNA double-strand breaks (DSBs) per cell, whereas ATM and initial Thr-68 phosphorylation occur at <8 DSBs, demonstrating that full CHEK2 activation requires a threshold level of DSBs distinct from ATM activation. Phospho-specific antibodies, gamma-irradiation dose-response, quantitative DSB measurement (comet assay/neutral elution) Oncogene Medium 15361830
2004 CHEK2 triggers replicative senescence in human fibroblasts: Chk2 is phosphorylated at sites of telomere-associated gamma-H2AX foci during senescence, and inactivation of CHEK2 reduces p21 expression and extends proliferative lifespan, placing CHEK2 in the telomere erosion-ATM-CHEK2-p53-p21 senescence pathway. Immunofluorescence, ChIP (gamma-H2AX at telomeres), CHEK2 inactivation with dominant-negative/siRNA, p21 western blot, proliferative lifespan assay EMBO Journal Medium 15192702
2005 ATM and CHEK2 phosphorylate MDMX on S342 and S367 (Chk2-dependent sites) after DNA damage, promoting MDMX degradation by MDM2 and p53 activation; Chk2 also stimulates MDMX ubiquitination and degradation. Mass spectrometry phosphosite identification, phospho-specific antibodies, RNAi knockdown, ubiquitination assay, p53 activity assay EMBO Journal High 16163388
2005 Wip1 phosphatase (PPM1D) associates with CHEK2 and dephosphorylates Thr-68 in vitro using purified proteins; in cells, wild-type but not phosphatase-dead Wip1 (D314A) inhibits Thr-68 phosphorylation and CHEK2 kinase activity; Wip1 RNAi leads to sustained Thr-68 phosphorylation, establishing Wip1 as a negative regulator of CHEK2. Co-immunoprecipitation, in vitro phosphatase assay with recombinant Wip1, site-directed mutagenesis, RNAi knockdown, phospho-specific western blot Cell Death and Differentiation High 16311512
2006 CHEK2 phosphorylates MDMX on Ser-367, stimulating MDMX binding to 14-3-3 proteins; this Chk2-mediated phosphorylation drives MDMX nuclear import via a cryptic NLS and promotes MDM2-mediated ubiquitination and degradation of MDMX, thereby enabling p53 activation. Co-immunoprecipitation, in vitro kinase assay, 14-3-3 binding assay, ubiquitination assay, nuclear localization imaging EMBO Journal High 16511560
2006 EDD (human orthologue of Drosophila hyperplastic discs) interacts with CHEK2 via the CHEK2 FHA domain and phospho-dependent binding; RNAi depletion of EDD impairs CHK2 activating phosphorylation after ionizing radiation or radiomimetics, establishing EDD as a novel mediator upstream of CHEK2 in DNA damage signaling. Co-immunoprecipitation (phospho-dependent), RNAi knockdown, in vitro kinase assay, phospho-specific western blot Journal of Biological Chemistry Medium 17074762
2006 PML interacts with CHEK2 and activates it by mediating its autophosphorylation step (an event required after initial ATM-mediated phosphorylation); PML/RARalpha in APL cells suppresses CHEK2 by dominantly inhibiting this autophosphorylation, but ATRA treatment restores CHEK2 autophosphorylation. Co-immunoprecipitation, in vitro kinase assay for autophosphorylation, ATRA treatment, dominant-negative analysis Journal of Biological Chemistry Medium 16835227
2007 CHEK2 phosphorylates HuR at residues S88, S100, and T118 upon oxidative stress; S100 phosphorylation is important for dissociation of the HuR-SIRT1 mRNA complex, triggering SIRT1 mRNA decay and reduced SIRT1 protein levels, linking CHEK2 to post-transcriptional gene regulation via mRNA stability. Co-immunoprecipitation, in vitro kinase assay (predicted phosphorylation sites), site-directed mutagenesis of HuR, RNA-binding/mRNA decay assay Molecular Cell Medium 17317627
2008 CHEK2 ubiquitination upon activation requires kinase activity and autophosphorylation on Ser-379; S379 is a novel IR-inducible autophosphorylation site required for ubiquitination by a Cullin-1-containing E3 ligase complex and is essential for CHEK2-induced apoptosis in response to DNA double-strand breaks. Phospho-site mutagenesis, ubiquitination assay, E3 ligase identification, apoptosis assay Molecular and Cellular Biology Medium 18644861
2008 CHEK2 has a p53-independent, DNA-damage-independent role in mitosis: depletion of CHEK2 or abrogation of its kinase activity causes abnormal mitotic spindle assembly, lagging chromosomes, chromosome missegregation, and chromosomal instability (CIN); BRCA1 is identified as a mitotic target of CHEK2 kinase, and loss of BRCA1 or its CHEK2-mediated phosphorylation also causes spindle defects. siRNA depletion, kinase-dead CHEK2 expression, immunofluorescence of mitotic spindles, karyotyping for CIN, live-cell imaging Nature Cell Biology High 20364141
2011 CHEK2-dependent HuR phosphorylation regulates occludin mRNA translation and intestinal epithelial barrier function: CHEK2 phosphorylates HuR enabling HuR binding to occludin mRNA 3'UTR and stimulating occludin translation; CHEK2 silencing or polyamine depletion reduces HuR-occludin mRNA association and impairs barrier function in vivo. RNA immunoprecipitation, siRNA knockdown, CHEK2 overexpression, mouse sepsis model (cecal ligation/puncture), western blot Nucleic Acids Research Medium 21745814
2013 The E3 ubiquitin ligase PIRH2 interacts with CHEK2, mediates its polyubiquitylation and proteasomal degradation in a phosphorylation-dependent manner; the deubiquitylase USP28 forms a complex with PIRH2 and CHEK2 and antagonizes PIRH2-mediated degradation; Pirh2-/- cells show CHEK2 accumulation and enhanced checkpoint activation, reversed by additional Chk2 deletion. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, Pirh2-/- and Pirh2-/-Chk2-/- double-knockout mouse cells, checkpoint assays Cell Death and Differentiation High 23449389
2014 CHEK2 is essential for eliminating oocytes bearing unrepaired meiotic DSBs or induced DSBs: Chk2 deficiency reverses female infertility caused by meiotic recombination mutations or irradiation; CHK2-dependent activation of p53 (TRP53) and p63 (TRP63) effects oocyte elimination; ATR signals to CHK2 as the primary upstream kinase in oocytes. Chk2-/- mouse genetics, meiotic recombination mutant crosses, irradiation of oocytes, genetic epistasis with p53/p63 knockouts Science High 24482479
2014 DNA-PKcs acts as the upstream kinase phosphorylating CHEK2 at Thr-68 during mitosis (not DNA damage response); this mitotic CHEK2 activation regulates the CHEK2-BRCA1 pathway to control microtubule dynamics, kinetochore attachment, and chromosomal segregation; loss of DNA-PKcs causes chromosome misalignment reversed by phosphomimetic CHEK2. DNA-PKcs depletion, phospho-specific antibody for Thr-68, phosphomimetic/phospho-dead CHEK2 rescue, live-cell imaging, chromosome segregation assay Oncogenesis Medium 24492479
2014 CHEK2 phosphorylates REGγ on Ser-247, increasing REGγ-DBC1 interaction; Chk2-mediated phosphorylation of REGγ promotes DBC1-SIRT1 binding and SIRT1 inhibition, leading to p53 acetylation and DBC1-induced apoptosis after DNA damage. Co-immunoprecipitation, siRNA knockdown, in vitro kinase assay, apoptosis assay, p53 acetylation western blot Nucleic Acids Research Medium 25361978
2015 CRAF phosphorylated on Ser-338 by PAK1 recruits CHEK2 and promotes CHEK2 phosphorylation/activation to enhance the DNA damage response and tumor radioresistance; this is a kinase-independent role for CRAF, and a phospho-mimetic CRAF-S338D mutant is sufficient to induce the CRAF-CHEK2 association. Co-immunoprecipitation with phospho-mimetic mutant, CHEK2 phosphorylation assay, allosteric CRAF inhibitor treatment, clonogenic survival after radiation Nature Communications Medium 26333361
2019 SIRT1 interacts with CHEK2, deacetylates it at lysine-520, which suppresses CHEK2 phosphorylation, dimerization, and activation; SIRT1 depletion causes CHEK2 hyperactivation-mediated cell cycle arrest; in vivo, Chk2 deletion rescues the neonatal lethality of Sirt1-/- mice, establishing SIRT1 as a negative regulator of CHEK2. Co-immunoprecipitation, deacetylation assay, phosphorylation assay, dimerization assay, Sirt1-/-Chk2-/- double-knockout mouse rescue Cell Death and Differentiation High 31209362
2020 CHK1 and CHK2 act in a semiredundant pathway to eliminate oocytes with unrepaired DSBs by signaling to p53 (TRP53) and the oocyte-exclusive isoform TAp63; CHK1 becomes more activated by persistent DSBs when CHK2 is absent, demonstrating kinase cross-talk in the oocyte DNA damage checkpoint. Chk2-/- and Chk1-conditional knockout mouse genetics, p53-/-p63-/- double-knockout oocyte rescue, phospho-western blot for CHK1/CHK2 activation Genetics High 32273296
2020 ARID1A targets non-chromatin substrate CHEK2 for ubiquitination by modulating RNF8 autoubiquitination; loss of ARID1A increases CHEK2 levels by reducing RNF8-mediated CHEK2 degradation, and CHK2 inhibition in ARID1A-deficient tumors leads to replication stress, cytosolic DNA accumulation, and STING-mediated innate immune activation. Proteomic analysis, Co-immunoprecipitation of ARID1A-CHEK2-RNF8, ubiquitination assay, STING pathway activation assay, in vivo tumor models Journal of Clinical Investigation Medium 33016929
2021 PCK1 loss promotes O-GlcNAcylation of CHEK2 at threonine-378, which counteracts CHEK2 stability and dimer formation, increases CHEK2-dependent Rb phosphorylation, and promotes HCC cell proliferation; metabolic reprogramming via oxaloacetate and AMPK-GFAT1 axis drives UDP-GlcNAc biosynthesis required for this modification. O-GlcNAcylation mapping by mass spectrometry, site-directed mutagenesis (Thr-378), Co-immunoprecipitation, Rb phosphorylation assay, PCK1-knockout mouse model, cell proliferation assay Journal of Clinical Investigation Medium 33690219
2021 CHEK2 regulates cellular energy metabolism by controlling succinate dehydrogenase (SDH) expression; DNA damage and elevated CHEK2 promote SDH activity and succinate oxidation through the TCA cycle, while cells with high CHEK2 rely more on glycolysis due to dysfunctional mitochondria; CHEK2 knockdown abolishes this metabolic reprogramming. NMR metabolomics, siRNA knockdown of CHEK2, SDH activity assay, mitochondrial function analysis, transgenic HCC mouse model Cancer Research Medium 33762357
2020 RTN3 facilitates p53 Ser-392 phosphorylation via CHEK2: RTN3 interacts with CHEK2, recruits it to the endoplasmic reticulum, and promotes CHEK2 activation in an ER calcium-dependent manner; HBV surface antigen competes with CHEK2 for RTN3 binding, blocking RTN3-mediated CHEK2/p53 activation. Co-immunoprecipitation, p53 phosphorylation assay, calcium chelation, RTN3-CHEK2-HBsAg competition binding, xenograft tumor model Gut Medium 33303565
2009 Persistent DNA damage signaling initiates inflammatory cytokine (IL-6) secretion (SASP) requiring ATM, NBS1, and CHK2 but not p53 or pRb; this demonstrates a novel role for CHEK2 in cellular communication of DNA damage state to surrounding tissue. siRNA knockdown of ATM/NBS1/CHK2 in senescent cells, cytokine ELISA, oncogene-induced senescence model Nature Cell Biology Medium 19597488
2007 ATR (not ATM) is the principal kinase activating CHEK2 during cisplatin treatment of renal cells; ATR is activated and co-localizes with H2AX at nuclear foci; downstream CHEK2 is phosphorylated and activated in an ATR-dependent manner and is required for p53 activation and apoptosis in cisplatin nephrotoxicity. Dominant-negative ATR/ATM expression, ATR-deficient fibroblasts, dominant-negative CHEK2, immunofluorescence co-localization, apoptosis assay, in vivo mouse model Journal of Biological Chemistry Medium 18162465
2004 A CHEK2 missense mutation (1368insA) causes cytoplasmic mislocalization of the encoded truncated protein in tumor sections and when ectopically expressed in cultured cells, establishing cytoplasmic sequestration as a novel mechanism to functionally disable CHEK2. Ectopic expression of mutant CHEK2-GFP, immunofluorescence in tumor sections, RT-PCR for splice variants Oncogene Medium 15361853
2001 A CHK2 R145W missense mutation found in Li-Fraumeni syndrome destabilizes the encoded protein, reducing its half-life from >120 min to ~30 min via proteasomal degradation; proteasome inhibitor treatment restores stability, identifying proteasomal degradation as a mechanism of CHEK2 inactivation. Protein half-life assay (cycloheximide chase), proteasome inhibitor (MG-132) treatment, western blot Cancer Research Medium 11719428
2017 CHK2 overexpression and mislocalisation to mitotic spindle structures promotes chromosome instability in HCC: CHK2 interacts with Aurora B kinase during mitosis for chromosome condensation/cytokinesis; the FHA domain of CHK2 is required for its mislocalisation to mitotic structures; CHK2 knockdown reverses lagging chromosomes and mitotic activity. Gain/loss-of-function, FHA domain mutagenesis, immunofluorescence/live imaging, Co-IP with Aurora B, karyotyping Gut Medium 28360097

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science (New York, N.Y.) 2519 17525332
2009 Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nature cell biology 1754 19597488
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer cell 1251 12781359
1997 Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science (New York, N.Y.) 1191 9278512
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2005 ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science (New York, N.Y.) 1109 15790808
1998 Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science (New York, N.Y.) 1094 9836640
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2000 DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science (New York, N.Y.) 1050 10710310
2010 The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Advances in cancer research 1018 21034966
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2004 Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Molecular cell 1014 15149599
2013 Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nature genetics 895 23535729
2002 Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature genetics 867 11967536
2001 The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 853 11298456
1999 The DNA sequence of human chromosome 22. Nature 808 10591208
2000 The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes & development 725 10673501
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1999 Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science (New York, N.Y.) 705 10617473
2000 Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proceedings of the National Academy of Sciences of the United States of America 699 10973490
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2000 Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes & development 618 10673500
2004 Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science (New York, N.Y.) 601 15064416
2017 Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. JAMA oncology 471 28418444
2007 Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Molecular cell 470 17317627
2003 Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer cell 456 12676583
2000 hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 449 10724175
2001 Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 444 11333986
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2004 CHEK2 is a multiorgan cancer susceptibility gene. American journal of human genetics 427 15492928
2010 A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nature genetics 422 20729852
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2004 CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. American journal of human genetics 386 15122511
2014 Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nature genetics 368 24880342
2002 Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. The EMBO journal 352 12356735
2014 CHK2 kinase in the DNA damage response and beyond. Journal of molecular cell biology 345 25404613
2003 Chk2 activates E2F-1 in response to DNA damage. Nature cell biology 335 12717439
1998 Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1. Nature 314 9774107
1998 Replication checkpoint enforced by kinases Cds1 and Chk1. Science (New York, N.Y.) 286 9572736
2000 Threonine 68 is required for radiation-induced phosphorylation and activation of Cds1. Nature cell biology 266 11025670
2004 Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Molecular and cellular biology 262 14701743
2007 ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. The Journal of biological chemistry 252 18162465
2007 CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Nature reviews. Cancer 243 18004398
1999 A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Current biology : CB 240 9889122
2003 Mutations in CHEK2 associated with prostate cancer risk. American journal of human genetics 238 12533788
2000 Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. Molecular and cellular biology 238 11073977
2014 Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science (New York, N.Y.) 234 24482479
2001 Mrc1 channels the DNA replication arrest signal to checkpoint kinase Cds1. Nature cell biology 207 11715017
2005 ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. The EMBO journal 205 16163388
2004 The Chk2 protein kinase. DNA repair 202 15279791
2002 PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nature cell biology 194 12402044
2000 Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways. Journal of cell science 179 11058076
1999 Cdc25 inhibited in vivo and in vitro by checkpoint kinases Cds1 and Chk1. Molecular biology of the cell 176 10198041
2001 Chk2 activation dependence on Nbs1 after DNA damage. Molecular and cellular biology 174 11438675
2005 Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase. Cell death and differentiation 168 16311512
2006 The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 150 16998506
2004 DNA damage checkpoint kinase Chk2 triggers replicative senescence. The EMBO journal 150 15192702
2020 CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. Cells 147 33322746
2005 p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2. Molecular cancer research : MCR 147 16317088
2003 Telomere attrition and Chk2 activation in human heart failure. Proceedings of the National Academy of Sciences of the United States of America 144 12702777
2000 Characterization of tumor-associated Chk2 mutations. The Journal of biological chemistry 144 11053450
2003 Swi1 prevents replication fork collapse and controls checkpoint kinase Cds1. Molecular and cellular biology 139 14560029
2001 Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer research 124 11719428
2015 Trial Watch: Targeting ATM-CHK2 and ATR-CHK1 pathways for anticancer therapy. Molecular & cellular oncology 122 27308506
1996 The CDS1 gene encoding CDP-diacylglycerol synthase in Saccharomyces cerevisiae is essential for cell growth. The Journal of biological chemistry 120 8557688
2010 The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nature cell biology 115 20364141
2005 Replication checkpoint kinase Cds1 regulates Mus81 to preserve genome integrity during replication stress. Genes & development 109 15805465
2008 The multiple checkpoint functions of CHK1 and CHK2 in maintenance of genome stability. Frontiers in bioscience : a journal and virtual library 106 18508566
2021 Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation. The Journal of clinical investigation 101 33690219
2006 Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3. The EMBO journal 100 16511560
2017 Current perspectives on CHEK2 mutations in breast cancer. Breast cancer (Dove Medical Press) 93 28553140
2020 Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors. The Journal of clinical investigation 92 33016929
2012 BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer 92 22811390
1999 Basis for the checkpoint signal specificity that regulates Chk1 and Cds1 protein kinases. Molecular and cellular biology 92 10330167
2004 Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. Oncogene 90 15361830
2011 Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function. Nucleic acids research 89 21745814
2002 Checking in on Cds1 (Chk2): A checkpoint kinase and tumor suppressor. BioEssays : news and reviews in molecular, cellular and developmental biology 83 12111733
2013 The effect of CHEK2 variant I157T on cancer susceptibility: evidence from a meta-analysis. DNA and cell biology 80 23713947
2002 Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Genes, chromosomes & cancer 79 11746983
2003 Replication checkpoint kinase Cds1 regulates recombinational repair protein Rad60. Molecular and cellular biology 77 12897162
2006 Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast. Genes & development 74 16618806
2019 SIRT1 modulates cell cycle progression by regulating CHK2 acetylation-phosphorylation. Cell death and differentiation 71 31209362
2004 Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Oncogene 70 15361853
2000 Response of Xenopus Cds1 in cell-free extracts to DNA templates with double-stranded ends. Molecular biology of the cell 70 10793133
2011 Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. European journal of cancer (Oxford, England : 1990) 69 21807500
2006 Chk2 molecular interaction map and rationale for Chk2 inhibitors. Clinical cancer research : an official journal of the American Association for Cancer Research 69 16675556
2012 Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Human molecular genetics 68 22419737
2007 Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts. International journal of cancer 68 17721994
2005 Targeting chk2 kinase: molecular interaction maps and therapeutic rationale. Current pharmaceutical design 67 16101442
2003 Karyopherin-alpha2 protein interacts with Chk2 and contributes to its nuclear import. The Journal of biological chemistry 66 12909615
2001 Mutation analysis of the CHK2 gene in families with hereditary breast cancer. British journal of cancer 65 11461078
2019 Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors. JAMA oncology 59 30676620
2008 Chk2 suppresses the oncogenic potential of DNA replication-associated DNA damage. Molecular cell 55 18614044
2006 DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response. Molecular and cellular biology 55 16478982
2006 EDD mediates DNA damage-induced activation of CHK2. The Journal of biological chemistry 52 17074762
2003 Allosteric effects mediate CHK2 phosphorylation of the p53 transactivation domain. EMBO reports 51 12897801
2001 Threonine-11, phosphorylated by Rad3 and atm in vitro, is required for activation of fission yeast checkpoint kinase Cds1. Molecular and cellular biology 50 11313465
2011 Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications. Breast cancer research : BCR 49 21542898
2007 Cross-talk between Chk1 and Chk2 in double-mutant thymocytes. Proceedings of the National Academy of Sciences of the United States of America 49 17360434
2008 Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention. Clinical genetics 48 19021634
2014 CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer. Prostate cancer 47 25431674
2010 Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo. The EMBO journal 47 20834228
2020 Oocyte Elimination Through DNA Damage Signaling from CHK1/CHK2 to p53 and p63. Genetics 45 32273296
2014 Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis. Nucleic acids research 45 25361978
2003 Determination of substrate specificity and putative substrates of Chk2 kinase. Biochemical and biophysical research communications 45 12711320
2006 Genetic and epigenetic analysis of CHEK2 in sporadic breast, colon, and ovarian cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 44 17145815
2020 Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus. Gut 43 33303565
2013 The E3 ligase PIRH2 polyubiquitylates CHK2 and regulates its turnover. Cell death and differentiation 43 23449389
2022 Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk. Cancer research 41 34903604
2015 Kinase-independent role for CRAF-driving tumour radioresistance via CHK2. Nature communications 41 26333361
2014 DNA-PKcs activates the Chk2-Brca1 pathway during mitosis to ensure chromosomal stability. Oncogenesis 40 24492479
2006 Promyelocytic leukemia activates Chk2 by mediating Chk2 autophosphorylation. The Journal of biological chemistry 40 16835227
2019 Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Human mutation 39 30851065
2017 CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression. Gut 39 28360097
2015 Genomic profiling of CHEK2*1100delC-mutated breast carcinomas. BMC cancer 38 26553136
2020 Cancer risk management among female BRCA1/2, PALB2, CHEK2, and ATM carriers. Breast cancer research and treatment 37 32445176
2019 SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway. Cancer medicine 37 30907073
2006 ATR, PML, and CHK2 play a role in arsenic trioxide-induced apoptosis. The Journal of biological chemistry 37 16891316
2002 CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis. Genes and immunity 37 11857062
2016 Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. Cancer genetics 36 27751358
2008 Role of CHK2 in cancer development. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 33 18796370
2021 DNA Damage Response Protein CHK2 Regulates Metabolism in Liver Cancer. Cancer research 32 33762357
2006 Characterization of CHEK2 mutations in prostate cancer. Human mutation 31 16835864
2022 Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies. Current hematologic malignancy reports 30 35674998
2008 Regulation of Chk2 ubiquitination and signaling through autophosphorylation of serine 379. Molecular and cellular biology 30 18644861
2004 Cds1 phosphorylation by Rad3-Rad26 kinase is mediated by forkhead-associated domain interaction with Mrc1. The Journal of biological chemistry 29 15173168
2004 Analysis of CHEK2 gene for ovarian cancer susceptibility. Gynecologic oncology 28 15385111