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FLASH GENE
Symbol CHEK2 contributors: mct/pgu - updated : 30-05-2017
HGNC name CHK2 checkpoint homolog (S. pombe)
HGNC id 16627
EXPRESSION
Type widely
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
blood / hematopoieticspleen   highly
Digestiveintestinelarge intestinecolon highly
Nervousbrain   lowly
Reproductivefemale systemuterus  lowly
 female systembreast  lowly
 female systemovary  highly
 male systemtestis  highly
 male systemprostate  lowly
Respiratorylung   lowly
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Blood / Hematopoietic    
Connective    
Lymphoid    
cells
SystemCellPubmedSpeciesStageRna symbol
Blood/Hematopoieticleukocyte
cell lineage lowly in germ cells
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • a ser/thr kinase domain
  • a forkhead associated (FHA) domain with potential binding site
  • conjugated ubiquitinated
    HOMOLOGY
    interspecies homolog to yeast S.cerevisiae RAD53,G
    homolog to yeast S.pombe Cds1
    homolog to murine Chk2/Rad53
    Homologene
    FAMILY
  • ser/THR family of protein kinases
  • CDS1 subfamily
  • CATEGORY enzyme , receptor membrane serine/threonine
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleoplasm,nuclear bodies,PML
    intracellular,nucleus,chromatin/chromosome,kinetochore
    text
  • binds centrosomes and arrests mitosis only after activation by ATM and ATR in response to DNA damage
  • localizes to kinetochores
  • basic FUNCTION
  • key cell cycle control gene encoding a pluripotent kinase that can cause arrest or apoptosis in response to unrepaired DNA damage
  • playing a central role in DNA damage response pathways
  • preventing cells containing damage DNA from entering mitosis
  • may have a role in meiosis
  • stabilizing TP53 by phosphorylation on serine 20 leading to cell cycle arrest in G1 in response to DNA damage
  • phosphorytating BRCA1 on serine 988,after DNA damage
  • nuclear phosphokinase responsible for the nuclear stabilization of TTC5
  • functions to maintain genome integrity after radiation-induced damage and has important implications for the use of Chk2 inhibitors as adjuvant cancer therapy
  • important transducer of DNA damage checkpoint signals, and its mutation contributes to hereditary and sporadic cancer
  • mediates the induction of senescence in fibroblasts, but is dispensable for the induction of telomere dysfunction checkpoints at the stem and progenitor cell level
  • CHEK2 centrosomal binding does not require DNA damage, but varies according to cell cycle progression
  • effector component of the ATM-dependent DNA damage response (DDR) pathway
  • critical regulator of the cellular DNA damage repair response
  • CHEK1 and CHEK2 cooperatively affect G1/S and intra-S phase checkpoints
  • is an essential mediator of the cellular responses to as an essential mediator of the cellular responses to RITA (reactivation of TP53 and induction of tumor cell apoptosis)
  • is a kinase that acts as a tumor suppressor gene
  • is a DNA damage checkpoint protein important for the ATM-TP53 signaling pathway
  • CHEK2 stabilizes TTK and phosphorylates AURKB-serine 331 to prevent mitotic exit when most kinetochores are unattached
  • role for CHEK2 in the signaling of dysfunctional telomeres
  • is a key component of the DNA damage response
  • participates in several molecular processes involved in DNA structure modification and cell cycle progression
  • activation of the checkpoint kinases CHEK1 and CHEK2 by DNA damage triggers cell cycle arrest and improved DNA repair, or apoptosis in case of excessive damage
  • during mitosis, BRCA1 and its positive regulator CHEK2 are localized at centrosomes and are required for the regulation of microtubule plus end assembly, thereby ensuring faithful mitosis and numerical chromosome stability
  • CELLULAR PROCESS cell cycle, checkpoint
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling signal transduction
    TP53 pathway
    a component component of multiple complexes involved in response to stress induced by DNA damage
    INTERACTION
    DNA
    RNA
    small molecule nucleotide,
    ATP binding
    protein
  • BRCA1, TP53
  • phosphorylating CDC25C phosphatase on Ser 216, to promote the binding of 14.3.3 (YWHAs) proteins, required for activation of the G2 checkpoint
  • PER3 physically interacted with ATM and CHEK2
  • EWSR1 depletion results in alternative splicing changes of genes involved in DNA repair and genotoxic stress signaling, including ABL1, CHEK2, and MAP4K2
  • BTBD12 has a crucial role in preventing excessive RAD9A-dependent activation of CHEK2 (23160493)
  • CHEK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11A (p110)
  • RCHY1 interacts with CHEK2 and mediates its polyubiquitylation and proteasomal degradation
  • NCOR2 is responsible for basal repression of PPM1D, a phosphatase that de-phosphorylates and inactivates CHEK2, thus affecting a feedback loop responsible for licensing the correct timing of CHEK2 activation and the proper execution of the DNA repair process
  • CHEK2 contributes to chromosomal stability through TTK
  • high levels of CEP72 counteract CHEK2 as a positive regulator of BRCA1 to ensure proper mitotic microtubule assembly
  • mitotic function of BRCA1 depends on its phosphorylation by the tumor-suppressor kinase CHEK2 and this regulation is required to ensure normal microtubule plus end assembly rates within mitotic spindles
  • dual molecular mechanism by which the CHEK2-BRCA1 axis restrains oncogenic AURKA activity during mitosis and BRCA1 itself is a target for AURKA relevant for chromosomal instability (CIN)
  • role for CHEK2 as a mediator of anoikis that functions through the regulation of AKT1S1 activation, which may be associated with the survival of circulating tumor cells and metastatic behavior
  • cell & other
    REGULATION
    activated by ATM dependent manner in response to DNA damage
    phosphorylation
    induced by PER3 (PER3 overexpression induced CHEK22 activation in the absence of exogenous DNA damage, and this activation depended on ATM
    Other CHEK2 inactivation in B cells leads to decreased Ig hypermutation and Ig class switching, and increased Ig gene conversion activity
    inactivation of CHEK2 reduces CCAR2-SIRT1 binding, thus preventing TP53 acetylation and CCAR2-induced apoptosis
    ASSOCIATED DISORDERS
    corresponding disease(s) LFS2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral germinal mutation      
    in prostate cancer
    tumoral germinal mutation      
    I157T missense mutation increases the risk of colorectal cancer , but the truncating mutations may confer a lower risk or no increase in risk
    tumoral germinal mutation     loss of function
    in patients with primary ovarian, fallopian tube, or peritoneal cancers
    Susceptibility
  • sarcoma, breast and prostate cancer, brain tumor, colon carcinoma (minor role), lung cancer
  • to risks of breast cancer
  • Variant & Polymorphism insertion/deletion , other
  • variant 1100delC increased in breast cancer
  • missense variant 1157T associated with increased risk of breast, colon, prostate, kidney, thyroid cancer
  • a large deletion associated to increased risk of cancer of prostate
  • (T/C) genotype was associated with a highly significantly lower incidence of lung cancer, with much greater absolute risk reduction in smokers than in non-smokers
  • risks of breast cancer associated with CHEK2 p.I157T and CHEK2 p.S428F are increased
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    dual inactivation of CHEK2 and MUS81 remarkably inhibits cancer
    ANIMAL & CELL MODELS
    CHK2 deficient mouse embryonic cells