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Showing CHEK2 — RAD53 is a alias.

CHEK2

Serine/threonine-protein kinase Chk2 · UniProt O96017

Length
543 aa
Mass
60.9 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 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

CHEK2 encodes a DNA-damage-activated serine/threonine checkpoint kinase, the mammalian homolog of yeast Rad53/Cds1, that is phosphorylated and activated downstream of ATM in response to genotoxic stress to coordinate cell cycle arrest, apoptosis, and senescence (PMID:9836640). Activation proceeds through ATM-mediated phosphorylation of Thr68, which drives FHA-domain-dependent oligomerization and trans-autophosphorylation of the activation-loop residues Thr383/Thr387; crystallographic analysis shows that productive dimerization is built from intermolecular phospho-Thr68–FHA, FHA–kinase, and FHA–FHA contacts that orient the two kinase active sites for transphosphorylation, and the Li-Fraumeni mutation Ile157 sits at the FHA–kinase interface where its mutation abolishes dimerization and activation (PMID:12024051, PMID:12805407, PMID:19782031). Once active, CHEK2 enforces checkpoints by phosphorylating Cdc25C on Ser216 and Cdc25A on Ser123, the latter triggering Cdc25A destruction to block CDK2 and DNA replication (PMID:9836640, PMID:11298456). CHEK2 is a principal activating kinase of the p53 axis: it phosphorylates p53 on Ser20 to disrupt Mdm2 binding and phosphorylates MDMX on Ser342/Ser367 to promote its 14-3-3 binding, nuclear import, and MDM2-mediated degradation, with Chk2-deficient cells failing to induce p53-dependent transcripts such as p21 and Noxa and resisting IR-induced apoptosis (PMID:10710310, PMID:12356735, PMID:16163388, PMID:16511560). Beyond classical checkpoint control, CHEK2 promotes autophagy by phosphorylating Beclin 1 (Ser90/Ser93) to disrupt the Beclin1-Bcl-2 complex and by phosphorylating FOXK1/FOXK2 to sequester them in the cytoplasm and de-repress ATG genes (PMID:32187724, PMID:31911943), and it drives replicative and p53-independent senescence through p21 induction at dysfunctional telomeres (PMID:15192702, PMID:16317088). CHEK2 activity is tuned by post-translational regulation—SIRT1 deacetylates Lys520 to suppress its dimerization and activation, while USP39 deubiquitinates and stabilizes the protein—and its nuclear import depends on karyopherin-alpha2 binding the NLS-3 motif (PMID:31209362, PMID:30771428, PMID:12909615). Genetically, CHEK2 suppresses tumorigenesis arising from S/G2-phase DNA damage (PMID:18614044).

Mechanistic history

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

    Established CHEK2 as the mammalian DNA-damage checkpoint kinase, answering how cells translate ATM signaling into a block on mitotic entry.

    Evidence In vitro kinase assay and cell-based phosphorylation showing ATM-dependent activation and Cdc25C Ser216 phosphorylation

    PMID:9836640

    Open questions at the time
    • Did not establish the full substrate repertoire
    • Mechanism of kinase activation not resolved
  2. 2000 High

    Connected CHEK2 to the p53 tumor-suppressor axis, defining how checkpoint kinase activity stabilizes p53 after damage.

    Evidence Knockout mouse cells, in vitro kinase assay, and transcriptional reporter showing p53 Ser20 phosphorylation and p21 induction

    PMID:10710310

    Open questions at the time
    • Did not quantify the relative contribution of Chk2 versus other p53 kinases
    • p53-independent functions not addressed
  3. 2001 High

    Defined the S-phase checkpoint mechanism by which CHEK2 halts replication, and linked tumor-associated alleles to substrate-binding failure.

    Evidence In vitro kinase assay with site mutagenesis and cell-based Cdc25A degradation after IR

    PMID:11298456

    Open questions at the time
    • In vivo contribution of the Cdc25A arm to tumor suppression not isolated
  4. 2002 High

    Resolved the activation mechanism, showing FHA-domain-driven oligomerization enables trans-autophosphorylation and kinase activation.

    Evidence Cell-free kinase assays, co-IP, mutagenesis, and chimeric dimerization constructs

    PMID:12024051

    Open questions at the time
    • Atomic geometry of the dimer not yet defined
    • Kinetics of oligomer assembly unresolved
  5. 2002 High

    Genetically separated which checkpoints and apoptotic programs depend on Chk2 in the intact animal.

    Evidence Knockout mice with flow cytometry, immunoblot, and qRT-PCR readouts after IR

    PMID:12356735

    Open questions at the time
    • Partial p53 stabilization implies redundant kinases not identified here
  6. 2003 High

    Mapped the activation phosphorylation cascade (Thr68 then activation-loop Thr383/387) and tied a Li-Fraumeni mutation to defective activation.

    Evidence In vitro and in vivo phosphorylation with phospho-specific antibodies and I157T mutant analysis

    PMID:12805407

    Open questions at the time
    • Functional consequence of Ser516 autophosphorylation not fully defined
  7. 2003 Medium

    Identified the nuclear import mechanism, showing karyopherin-alpha2 recognizes the NLS-3 motif to localize CHEK2 to the nucleus.

    Evidence Yeast two-hybrid, GST pulldown, co-IP, and NLS mutagenesis with microscopy

    PMID:12909615

    Open questions at the time
    • Regulation of import in response to damage not addressed
    • Single-lab interaction not reciprocally validated in vivo
  8. 2005 High

    Extended CHEK2's p53-activating role to MDMX, showing it triggers MDMX degradation upstream of p53 accumulation.

    Evidence Co-IP, mass spectrometry site mapping, RNAi, and ubiquitination assays for Ser342/Ser367

    PMID:16163388 PMID:16511560

    Open questions at the time
    • Quantitative contribution of MDMX degradation relative to direct p53 phosphorylation unresolved
  9. 2009 High

    Provided the structural basis for FHA-mediated dimerization and explained why Ile157 mutation abolishes activation.

    Evidence X-ray crystallography of dimeric CHK2 with biochemical mutagenesis and kinase assays

    PMID:19782031

    Open questions at the time
    • Structure does not capture the full-length damage-activated complex in cells
  10. 2008 Medium

    Broadened upstream activation beyond ATM, implicating DNA-PK, ATR, and EDD as context-dependent activators of CHEK2.

    Evidence In vitro kinase assays with purified DNA-PK, DNA-PKcs/ATR-deficient cells, RNAi, and co-IP across separate studies

    PMID:15668230 PMID:17074762 PMID:18162465

    Open questions at the time
    • Relative weighting of ATM/ATR/DNA-PK across damage types not unified
    • EDD mechanism of activation not mapped to specific phosphosites
  11. 2008 Medium

    Defined the tumor-suppressive niche of CHEK2 within the MRN-checkpoint network through genetic epistasis.

    Evidence Compound knockout mouse genetics with tumor incidence and apoptosis readouts

    PMID:18614044

    Open questions at the time
    • Molecular basis of the S/G2-specific suppression not delineated
  12. 2019 High

    Revealed reciprocal post-translational control of CHEK2 abundance and activity via USP39 stabilization and SIRT1 deacetylation.

    Evidence Deubiquitination/deacetylation assays, mutagenesis, knockdown, and Sirt1/Chk2 double-knockout genetic epistasis

    PMID:30771428 PMID:31209362

    Open questions at the time
    • Conditions selecting deacetylation versus deubiquitination not defined
    • Acetyltransferase opposing SIRT1 at Lys520 not identified
  13. 2020 Medium

    Established CHEK2 as a direct driver of autophagy through Beclin 1 and FOXK1/2 phosphorylation, extending its role beyond cell cycle control.

    Evidence In vitro kinase assays with mutagenesis, co-IP, fractionation, reporter assays, and Chk2-knockout stroke model

    PMID:31911943 PMID:32187724

    Open questions at the time
    • Integration of autophagic and checkpoint outputs in the same cell unresolved
    • FOXK arm validated in single lab
  14. 2021 Medium

    Linked CHEK2 to metabolic reprogramming, showing it modulates succinate dehydrogenase and a glycolytic shift after DNA damage.

    Evidence siRNA knockdown with NMR metabolic profiling, mitochondrial assays, and a transgenic HCC mouse model

    PMID:33762357

    Open questions at the time
    • Direct substrate mediating SDH control not identified
    • Single-lab metabolic mechanism

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CHEK2 partitions its activated pool among checkpoint, apoptotic, autophagic, senescence, and metabolic outputs in a given cell remains unresolved.
  • No quantitative model of substrate selection downstream of activation
  • Determinants of upstream kinase (ATM/ATR/DNA-PK) choice not unified
  • Coordination of nuclear versus centrosomal/mitochondrial functions unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 2
Localization
GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-73894 DNA Repair 3 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2
Partners
BECN1CDC25ACDC25CKPNA2MDM4SIRT1TP53USP39

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 CHEK2 (Chk2) is the mammalian homolog of yeast Rad53/Cds1 and is phosphorylated and activated in response to DNA damage in an ATM-dependent manner; in vitro, Chk2 phosphorylates Cdc25C on serine-216, a site involved in negative regulation of Cdc25C, implicating Chk2 in preventing mitotic entry after DNA damage. In vitro kinase assay, co-immunoprecipitation, cell-based phosphorylation assay Science High 9836640
2000 Chk2 directly phosphorylates p53 on serine-20, which interferes with Mdm2 binding and promotes p53 stabilization; Chk2-deficient mouse cells fail to stabilize p53 or induce p53-dependent transcripts (p21) after gamma-irradiation, and reintroduction of Chk2 restores p53-dependent transcription. Gene targeting (knockout mouse), in vitro kinase assay, transcriptional reporter assay, gamma-irradiation Science High 10710310
2001 Chk2 phosphorylates Cdc25A on serine-123 downstream of ATM in response to ionizing radiation, triggering Cdc25A destruction, preventing Cdk2 dephosphorylation, and blocking DNA replication (S-phase checkpoint); tumor-associated Chk2 alleles cannot bind or phosphorylate Cdc25A. In vitro kinase assay, phosphorylation site mutagenesis, cell-based degradation assay, IR treatment Nature High 11298456
2002 Chk2-deficient mice show resistance to IR-induced apoptosis in thymocytes and neurons; the IR-induced G1/S checkpoint is impaired in Chk2-/- embryonic fibroblasts, while G2/M and S-phase checkpoints are less affected; p53 stabilization is partially reduced, and p53-dependent transcription of p21 and Noxa is abolished in Chk2-/- cells. Gene targeting (knockout mouse), flow cytometry, immunoblot, qRT-PCR The EMBO journal High 12356735
2002 Chk2 undergoes ATM-dependent phosphorylation-dependent oligomerization after DNA damage; oligomerization requires the FHA domain of one Chk2 molecule to interact with the SQ/TQ cluster domain (SCD) of another; oligomers allow trans-autophosphorylation and kinase activation, and induced oligomerization alone augments Chk2 kinase activity. Cell-free system kinase assay, co-immunoprecipitation, mutagenesis, oligomerization/size exclusion analysis, chimeric Chk2 dimerization construct Molecular and cellular biology High 12024051
2003 ATM phosphorylates Chk2 at Thr68, promoting oligomerization and subsequent autophosphorylation of the activation loop at Thr383 and Thr387; Ser516 is an additional IR-inducible autophosphorylation site; the Li-Fraumeni mutation I157T impairs Chk2 oligomerization and autophosphorylation. In vitro kinase assay, in vivo phosphorylation with mutant cell lines, phospho-specific antibodies, mutagenesis Molecular cancer research High 12805407
2009 Crystal structure of dimeric CHK2 reveals that productive dimerization involves intermolecular phosphoThr68-FHA interactions, FHA-kinase domain interactions, and FHA-FHA interactions; in the dimer, kinase active sites face each other for efficient activation-loop transphosphorylation; Ile157, mutated in Li-Fraumeni syndrome, is central to the FHA-kinase domain interface and its mutation abolishes dimerization and autophosphorylation. X-ray crystallography, biochemical mutagenesis, kinase activity assays Molecular cell High 19782031
2005 Chk2 phosphorylates MDMX on Ser342 and Ser367 in vivo, stimulating MDMX ubiquitination and degradation by MDM2 following DNA damage, contributing to p53 activation; ATM-dependent degradation of MDMX precedes p53 accumulation. Co-immunoprecipitation, mass spectrometry, phospho-specific antibodies, RNAi knockdown, ubiquitination assay The EMBO journal High 16163388
2006 Chk2-mediated phosphorylation of MDMX on Ser367 promotes 14-3-3 binding, MDMX nuclear import via a cryptic nuclear localization signal, and subsequent MDM2-mediated MDMX degradation; mutation of MDMX Ser367 inhibits ubiquitination, degradation, and nuclear import; 14-3-3 and Chk2 cooperatively stimulate MDMX ubiquitination. Co-immunoprecipitation/co-purification, mutagenesis, immunofluorescence, ubiquitination assay, nuclear fractionation The EMBO journal High 16511560
2003 Karyopherin-alpha2 (KPNA-2) interacts with Chk2 through the Chk2 NLS-3 motif (amino acids 515-522); this interaction is required for Chk2 nuclear import, as mutations in NLS-3 (but not NLS-1 or NLS-2) cause cytoplasmic relocalization of Chk2. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, mutagenesis, fluorescence microscopy The Journal of biological chemistry Medium 12909615
2002 Chk2 co-localizes with and co-immunoprecipitates Polo-like kinase 1 (Plk1); Plk1 overexpression enhances Chk2 phosphorylation at Thr68; Plk1 phosphorylates recombinant Chk2 in vitro; Chk2 phosphorylated at Thr68 and Thr26/Ser28 is present at centrosomes and midbodies in the absence of DNA damage. Co-immunoprecipitation, in vitro kinase assay, indirect immunofluorescence The Journal of biological chemistry Medium 12493754
2005 DNA-dependent protein kinase (DNA-PK) can phosphorylate Chk2 at Thr68 in vitro; endogenous Chk2 co-immunoprecipitates Ku70 and Ku80; in cells lacking functional DNA-PKcs, IR-induced Chk2 phosphorylation is consistently diminished; DNA-PK augments ATM and ATR in activating Chk2 after DNA damage. In vitro kinase assay with purified DNA-PK, co-immunoprecipitation, siRNA knockdown, matched cell lines with/without functional DNA-PK The Journal of biological chemistry Medium 15668230
2000 Tumor-associated Chk2 FHA domain mutations: R145W retains basal kinase activity but cannot be phosphorylated at ATM-dependent Thr68 and cannot be activated by gamma-irradiation, and forms a larger aberrant complex in cells; wild-type Chk2 exists in a complex of ~200 kDa. Another FHA mutation I157T behaves similarly to wild-type in all biochemical assays tested. In vitro kinase assay, immunoprecipitation, gel filtration, gamma-irradiation The Journal of biological chemistry Medium 11053450
2004 Chk2 is required for replicative senescence in human fibroblasts: Chk2 is phosphorylated and activated at short dysfunctional telomeres; inactivation of Chk2 reduces p21(waf1) expression and extends proliferative lifespan, consistent with failure to activate p53. Immunofluorescence, immunoblot, siRNA knockdown, proliferation assay The EMBO journal Medium 15192702
2006 EDD (human orthologue of Drosophila hyperplastic discs) associates with CHK2 through a phospho-dependent interaction involving the CHK2 FHA domain and EDD threonine residues; RNAi depletion of EDD impairs CHK2 activating phosphorylation and kinase activity in response to IR, identifying EDD as a mediator upstream of CHK2. Co-immunoprecipitation, RNAi knockdown, in vitro kinase assay, IR treatment The Journal of biological chemistry Medium 17074762
2008 TRAIL-induced apoptosis activates Chk2 phosphorylation downstream of the mitochondrial death pathway; Chk2 phosphorylation is dependent on both ATM and DNA-PK; downregulation of Chk2 delays activation of caspases 2, 3, 8, and 9 and reduces TRAIL-induced cell killing, indicating Chk2 acts as a positive feedback amplifier of the apoptotic response. Immunofluorescence, siRNA knockdown, caspase activity assay, co-localization microscopy Molecular and cellular biology Medium 18955500
2007 ATR (not ATM or DNA-PK) is the critical upstream activator of Chk2 in cisplatin-induced apoptosis in renal cells; both Chk1 and Chk2 are phosphorylated in an ATR-dependent manner; Chk2 inhibition (dominant-negative or gene deficiency) attenuates cisplatin-induced p53 activation and apoptosis; in vivo, ATR and Chk2 are activated in renal tissues after cisplatin treatment. Dominant-negative mutant expression, ATR-deficient fibroblasts, siRNA, immunofluorescence, in vivo mouse model The Journal of biological chemistry Medium 18162465
2019 SIRT1 directly interacts with CHK2, deacetylates CHK2 at lysine 520, which suppresses CHK2 phosphorylation, dimerization, and activation; SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest and cell death; genetic deletion of Chk2 rescues neonatal lethality of Sirt1-/- mice. Co-immunoprecipitation, deacetylation assay, mutagenesis, mouse genetic epistasis (Sirt1-/-;Chk2-/- double knockout) Cell death and differentiation High 31209362
2019 USP39 deubiquitinates and stabilizes CHK2 protein; USP39 knockdown reduces CHK2 levels and compromises DNA damage-induced G2/M checkpoint activation, apoptosis, and sensitizes cells to chemotherapy and radiation. shRNA knockdown, ubiquitination assay, immunoblot, flow cytometry (G2/M checkpoint), cell survival assay Cancer letters Medium 30771428
2020 CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, impairing Beclin 1-Bcl-2 complex formation in a ROS-dependent fashion and thereby promoting autophagy; CHK2-/- mice show aggravated infarct phenotypes and reduced Beclin 1 phosphorylation in a cerebral stroke model. Co-immunoprecipitation, in vitro kinase assay with mutagenesis, Chk2 knockout mice, cerebral stroke in vivo model The EMBO journal High 32187724
2020 CHK2 phosphorylates FOXK1 and FOXK2, creating a 14-3-3γ binding site that traps FOXK proteins in the cytoplasm, thereby de-repressing ATG gene transcription and promoting autophagy in response to DNA damage. Co-immunoprecipitation, in vitro kinase assay, subcellular fractionation, reporter assay, mutagenesis Science advances Medium 31911943
2014 Chk2 phosphorylates REGγ on Ser247, increasing REGγ-DBC1 interaction, which in turn inhibits SIRT1 and promotes p53 acetylation and apoptosis in response to DNA damage; Chk2 inactivation reduces DBC1-SIRT1 binding and prevents p53 acetylation. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, acetylation assay Nucleic acids research Medium 25361978
2008 Chk2 deficiency does not modify checkpoint defects or chromosomal instability of Mre11 complex mutants, but Nbs1-/Chk2- and Mre11-/Chk2- double mutant mice show synergistic defects in DNA-damage-induced p53 regulation and apoptosis and are predisposed to tumors; Chk2 specifically suppresses oncogenic potential of DNA damage arising during S and G2 phases. Compound knockout mouse genetics, epistasis analysis, tumor incidence, apoptosis assays Molecular cell Medium 18614044
2001 Chk2 protein is stable, nuclear, and activatable throughout the cell cycle including in quiescent and differentiating cells; in human tissues, Chk2 expression is homogeneous in renewing cell populations, heterogeneous in conditionally renewing tissues, and absent or cytoplasmic in static tissues such as muscle or brain. Immunohistochemistry, immunofluorescence, subcellular fractionation, Western blot across cell cycle phases Cancer research Medium 11431331
2003 A truncated CHK2 protein encoded by a novel 1368insA mutation is stable yet mislocalizes to the cytoplasm both in tumor sections and when ectopically expressed in cultured cells, indicating that cytoplasmic sequestration is a mechanism to disable CHK2 function. Ectopic expression, immunofluorescence/immunohistochemistry in tumor sections Oncogene Low 15361853
2014 DNA-PKcs is the upstream regulator of Chk2 phosphorylation at Thr68 during mitosis; Chk2 activates BRCA1, which promotes monoubiquitination of γ-tubulin to inhibit microtubule nucleation; loss of DNA-PKcs results in chromosome misalignment rescued by phosphomimetic Chk2 or BRCA1. siRNA knockdown, phosphomimetic mutant rescue, immunofluorescence, co-immunoprecipitation Oncogenesis Medium 24492479
2015 CRAF pSer338 recruits CHK2 and promotes CHK2 phosphorylation/activation to enhance the DNA damage response and tumor radioresistance; a phospho-mimetic CRAF S338D mutant is sufficient to induce CRAF/CHK2 association. Co-immunoprecipitation, phosphorylation assay, phospho-mimetic mutant, allosteric inhibitor Nature communications Medium 26333361
2005 Chk2-dependent induction of p21(Waf1/Cip1) and senescence can occur in p53-defective cells; siRNA-mediated knockdown of p21 in p53-defective cells expressing Chk2 reduces senescence, establishing a p53-independent pathway for Chk2-driven senescence. Viral transduction of Chk2, siRNA knockdown of p21, senescence assays in p53-defective cell lines Molecular cancer research Medium 16317088
2020 CHK2 is required for elimination of oocytes with unrepaired meiotic DSBs; both CHK1 and CHK2 become activated by persistent DSBs in oocytes; oocytes lacking both p53 and TAp63 are nearly fully protected from elimination, placing CHK1/CHK2 upstream of TRP53/TAp63 in a semiredundant oocyte elimination pathway. Genetic epistasis with knockout mice (Chk2-/-, p53-/-, TAp63-/-, Spo11-/-, Trip13-/-), histological analysis Genetics Medium 32273296
2021 CHK2 controls expression of succinate dehydrogenase (SDH) and intervenes with mitochondrial functions; DNA damage and CHK2 promote SDH activity and increased succinate oxidation through the TCA cycle; cells with DNA damage and elevated CHK2 rely on glycolysis for ATP production due to dysfunctional mitochondria; CHK2 knockdown abolishes this metabolic shift. siRNA knockdown, metabolic profiling (NMR), mitochondrial function assays, transgenic HCC mouse model Cancer research Medium 33762357

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer cell 1252 12781359
1998 Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science (New York, N.Y.) 1096 9836640
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 1026 21034966
2001 The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 857 11298456
2001 Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 575 11484057
1998 A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature 539 9783589
1999 Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms. Science (New York, N.Y.) 459 10550056
2001 Mrc1 transduces signals of DNA replication stress to activate Rad53. Nature cell biology 430 11715016
1994 The SAD1/RAD53 protein kinase controls multiple checkpoints and DNA damage-induced transcription in yeast. Genes & development 427 7958905
2009 Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. Current opinion in cell biology 405 19230643
2002 Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. The EMBO journal 353 12356735
2014 CHK2 kinase in the DNA damage response and beyond. Journal of molecular cell biology 351 25404613
2001 CHK2 kinase--a busy messenger. Nature reviews. Molecular cell biology 344 11733767
1998 Rad53 FHA domain associated with phosphorylated Rad9 in the DNA damage checkpoint. Science (New York, N.Y.) 328 9657725
1996 Spk1/Rad53 is regulated by Mec1-dependent protein phosphorylation in DNA replication and damage checkpoint pathways. Genes & development 282 8600024
2003 A Rad53 kinase-dependent surveillance mechanism that regulates histone protein levels in S. cerevisiae. Cell 268 14651846
2007 ATR-Chk2 signaling in p53 activation and DNA damage response during cisplatin-induced apoptosis. The Journal of biological chemistry 254 18162465
2007 CHK2 kinase: cancer susceptibility and cancer therapy - two sides of the same coin? Nature reviews. Cancer 244 18004398
1999 Cdc7p-Dbf4p kinase binds to chromatin during S phase and is regulated by both the APC and the RAD53 checkpoint pathway. The EMBO journal 223 10508166
2005 ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. The EMBO journal 206 16163388
2004 The Chk2 protein kinase. DNA repair 202 15279791
2002 Rad9 phosphorylation sites couple Rad53 to the Saccharomyces cerevisiae DNA damage checkpoint. Molecular cell 194 12049741
2002 Chk2 activation and phosphorylation-dependent oligomerization. Molecular and cellular biology 162 12024051
2006 The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 153 16998506
2004 DNA damage checkpoint kinase Chk2 triggers replicative senescence. The EMBO journal 151 15192702
2020 CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. Cells 149 33322746
2005 p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2. Molecular cancer research : MCR 147 16317088
2000 Characterization of tumor-associated Chk2 mutations. The Journal of biological chemistry 144 11053450
2009 Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase. Molecular cell 142 19782031
2003 Regulation of the Chk2 protein kinase by oligomerization-mediated cis- and trans-phosphorylation. Molecular cancer research : MCR 137 12805407
2002 Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody. The Journal of biological chemistry 133 12493754
2015 Trial Watch: Targeting ATM-CHK2 and ATR-CHK1 pathways for anticancer therapy. Molecular & cellular oncology 122 27308506
2020 ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress. The EMBO journal 114 32187724
2001 DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. Cancer research 112 11431331
2008 The multiple checkpoint functions of CHK1 and CHK2 in maintenance of genome stability. Frontiers in bioscience : a journal and virtual library 106 18508566
2006 Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3. The EMBO journal 100 16511560
2006 The Rad53 signal transduction pathway: Replication fork stabilization, DNA repair, and adaptation. Experimental cell research 97 16859682
2017 Current perspectives on CHEK2 mutations in breast cancer. Breast cancer (Dove Medical Press) 94 28553140
2003 Rad53 phosphorylation site clusters are important for Rad53 regulation and signaling. Molecular and cellular biology 92 12917350
2008 Death receptor-induced activation of the Chk2- and histone H2AX-associated DNA damage response pathways. Molecular and cellular biology 91 18955500
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 81 23713947
2005 Regulation of CHK2 by DNA-dependent protein kinase. The Journal of biological chemistry 80 15668230
1999 Role of human Cds1 (Chk2) kinase in DNA damage checkpoint and its regulation by p53. The Journal of biological chemistry 80 10531348
2005 The conserved Mec1/Rad53 nuclear checkpoint pathway regulates mitochondrial DNA copy number in Saccharomyces cerevisiae. Molecular biology of the cell 78 15829566
2008 Rad53 regulates replication fork restart after DNA damage in Saccharomyces cerevisiae. Genes & development 75 18628397
2006 An FHA domain-mediated protein interaction network of Rad53 reveals its role in polarized cell growth. The Journal of cell biology 74 17130285
2019 SIRT1 modulates cell cycle progression by regulating CHK2 acetylation-phosphorylation. Cell death and differentiation 73 31209362
2004 Alternative splicing and mutation status of CHEK2 in stage III breast cancer. Oncogene 70 15361853
2012 Response to DNA damage of CHEK2 missense mutations in familial breast cancer. Human molecular genetics 69 22419737
2005 Signal transduction: how rad53 kinase is activated. Current biology : CB 69 16169479
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
2008 Diphosphothreonine-specific interaction between an SQ/TQ cluster and an FHA domain in the Rad53-Dun1 kinase cascade. Molecular cell 63 18570878
2019 USP39 regulates DNA damage response and chemo-radiation resistance by deubiquitinating and stabilizing CHK2. Cancer letters 60 30771428
2012 DNA replication stress differentially regulates G1/S genes via Rad53-dependent inactivation of Nrm1. The EMBO journal 58 22333915
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
2020 CHK2-FOXK axis promotes transcriptional control of autophagy programs. Science advances 54 31911943
2007 Mechanisms of checkpoint kinase Rad53 inactivation after a double-strand break in Saccharomyces cerevisiae. Molecular and cellular biology 53 17325030
2006 EDD mediates DNA damage-induced activation of CHK2. The Journal of biological chemistry 53 17074762
2020 Rad53 limits CMG helicase uncoupling from DNA synthesis at replication forks. Nature structural & molecular biology 52 32341532
2015 Rad53-Mediated Regulation of Rrm3 and Pif1 DNA Helicases Contributes to Prevention of Aberrant Fork Transitions under Replication Stress. Cell reports 50 26411679
2015 Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity. PLoS genetics 49 26584331
2003 FHA domain-mediated DNA checkpoint regulation of Rad53. Cell cycle (Georgetown, Tex.) 49 12851493
2020 Oocyte Elimination Through DNA Damage Signaling from CHK1/CHK2 to p53 and p63. Genetics 47 32273296
2014 CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer. Prostate cancer 47 25431674
2003 Determination of substrate specificity and putative substrates of Chk2 kinase. Biochemical and biophysical research communications 46 12711320
2014 Chk2 and REGγ-dependent DBC1 regulation in DNA damage induced apoptosis. Nucleic acids research 45 25361978
2008 Distinct phosphatases mediate the deactivation of the DNA damage checkpoint kinase Rad53. The Journal of biological chemistry 45 18441009
2002 Mutation analysis of the CHK2 gene in breast carcinoma and other cancers. Breast cancer research : BCR 45 12052256
2008 Role of the Saccharomyces cerevisiae Rad53 checkpoint kinase in signaling double-strand breaks during the meiotic cell cycle. Molecular and cellular biology 44 18505828
2015 Sae2 promotes DNA damage resistance by removing the Mre11-Rad50-Xrs2 complex from DNA and attenuating Rad53 signaling. Proceedings of the National Academy of Sciences of the United States of America 43 25831494
2015 Kinase-independent role for CRAF-driving tumour radioresistance via CHK2. Nature communications 42 26333361
2014 DNA-PKcs activates the Chk2-Brca1 pathway during mitosis to ensure chromosomal stability. Oncogenesis 41 24492479
2003 Rad53 checkpoint kinase phosphorylation site preference identified in the Swi6 protein of Saccharomyces cerevisiae. Molecular and cellular biology 41 12724400
2000 II. Structure and specificity of the interaction between the FHA2 domain of Rad53 and phosphotyrosyl peptides. Journal of molecular biology 41 10993733
2021 Rad53 checkpoint kinase regulation of DNA replication fork rate via Mrc1 phosphorylation. eLife 40 34387546
2019 Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Human mutation 40 30851065
2022 CHEK2 variants: linking functional impact to cancer risk. Trends in cancer 39 35643632
2017 CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression. Gut 39 28360097
2009 Reconstitution of Rad53 activation by Mec1 through adaptor protein Mrc1. The Journal of biological chemistry 39 19457865
2015 Genomic profiling of CHEK2*1100delC-mutated breast carcinomas. BMC cancer 38 26553136
2019 SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway. Cancer medicine 37 30907073
2002 A robust method for detecting CHK2/RAD53 mutations in genomic DNA. Human mutation 37 11793476
2010 CHEK2 mutations and HNPCC-related colorectal cancer. International journal of cancer 36 19876921
2006 Targeted gene repair activates Chk1 and Chk2 and stalls replication in corrected cells. DNA repair 35 16414312
2005 Activation of the checkpoint kinase Rad53 by the phosphatidyl inositol kinase-like kinase Mec1. The Journal of biological chemistry 35 16365046
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
2022 Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies. Current hematologic malignancy reports 32 35674998
2021 DNA Damage Response Protein CHK2 Regulates Metabolism in Liver Cancer. Cancer research 32 33762357
2014 DNA-PK/Chk2 induces centrosome amplification during prolonged replication stress. Oncogene 31 24662822
2010 Regulation of tolerance to DNA alkylating damage by Dot1 and Rad53 in Saccharomyces cerevisiae. DNA repair 31 20674515
2020 Roles of Chk2/CHEK2 in guarding against environmentally induced DNA damage and replication-stress. Environmental and molecular mutagenesis 30 32578892
2019 Rad53- and Chk1-Dependent DNA Damage Response Pathways Cooperatively Promote Fungal Pathogenesis and Modulate Antifungal Drug Susceptibility. mBio 30 30602579
2021 Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers. Genes 28 33919281
2018 Helicase Subunit Cdc45 Targets the Checkpoint Kinase Rad53 to Both Replication Initiation and Elongation Complexes after Fork Stalling. Molecular cell 28 30595439

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