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FLASH GENE
Symbol CHEK1 contributors: mct/pgu - updated : 03-09-2016
HGNC name CHK1 checkpoint homolog (S. pombe)
HGNC id 1925
Location 11q24.2      Physical location : 125.495.035 - 125.546.148
Synonym name
  • checkpoint kinase 1
  • serine/threonine-protein kinase Chk1
  • Synonym symbol(s) CHK1
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 51.12 kb     14 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    14 - 2699 54.4 476 - 1997 9382850
    13 - 4174 54.4 476 - 1997 9382850
    13 - 3517 54.4 476 - 1997 9382850
    12 - 4072 50.4 442 - 1997 9382850
    10 splicing 1393 43.7 384 . widely . low in G1-phase cells and higher in G1/S and G2/M cells . can localize to centrosomes, providing a spatial and temporal regulation of CHEK1 to initiate mitotic entry 2012 22184239
  • N-terminally truncated splice variant of CHEK1
  • may be one of the key endogenous repressing factors for CHEK1
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticthymus   highly
    Digestiveintestinesmall intestine   
     intestinelarge intestinecolon  
    Reproductivemale systemtestis   
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Reproductiveoocyte Mus musculus
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    cell cycle     cell cycle, checkpoint, G2M
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • nine consecutive adenine in the coding region
  • two highly conserved motifs (CM1 and CM2) at the C terminus, functionning as a nuclear export signal and nuclear localization signal, respectively
  • HOMOLOGY
    interspecies homolog to yeast S.pombe rad3
    homolog to murine Chek1
    Homologene
    FAMILY
  • protein kinase superfamily
  • PI3/PI4 family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,nucleoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • histone H3 kinase that regulates transcriptional repression in response to DNA damage
  • required for cell cycle arrest in reponse to DNA damage, in association with 14.3.3 proteins (YWHA*)
  • involved in negative regulation of cell proliferation
  • activates FANC/BRCA pathway through FANCD2 monoubiquitination
  • acts as an integrator for Atm and Atr signals and may be involved in monitoring the processing of meiotic recombination
  • playing a role in regulating claspin stability in the cell
  • protects vertebrate cells against spontaneous chromosome missegregation and is required to sustain anaphase delay when spindle function is disrupted by taxol
  • could protect against tumorigenesis through its role in spindle checkpoint signaling
  • regulates the ubiquitination of PCNA with the help of claspin and timeless proteins
  • activating NEK11 via phosphorylation on ser273
  • may promotes replication fork progression during normal S phase by controlling replication origin activity
  • role in suppressing origin firing may also explain its role in promoting replication elongation
  • CHEK1 and CHEK2 cooperatively affect G1/S and intra-S phase checkpoints
  • critical effector of DNA damage checkpoints necessary for the maintenance of chromosome integrity during cell cycle progression
  • implicated in a circuit in which it activates checkpoints, DNA repair and proliferating cell nuclear antigen and FANCD2 monoubiquitinylation
  • existence of a circuit in which CHEK1 activates checkpoints, DNA repair and proliferating cell nuclear antigen and FANCD2 monoubiquitinylation
  • key regulator of checkpoint signaling in both the unperturbed cell cycle and DNA damage response
  • key regulator of mitotic entry or the S-to-G2/M transition in the cell cycle
  • is potentially indispensable for prophase I arrest and functions in G 2/M checkpoint regulation in meiotic oocytes
  • important effector kinase that regulates the cell cycle checkpoint
  • CHEK1 and MAD2L1 crosstalk in the DNA damage checkpoint and in the mitotic spindle checkpoint
  • BTG3-dependent CHEK1 ubiquitination contributes to its chromatin localization and activation and a defect in this regulation may increase genome instability and promote tumorigenesis
  • CHEK1 both arrests replication forks and enhances repair of DNA damage by phosphorylation of downstream effectors
  • BRCA1, FANCD2 and CHEK1 are potential targets for the modulation of radiation response in bystander cells
  • 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
  • negatively regulates Ig somatic hypermutation by promoting error-free homologous recombination and Ig gene conversion
  • phosphorylates chromatin-bound proteins and even holds kinase-independent functions might shed light on how CHEK1 contributes to the elongation of damaged DNA
  • is a multifaceted and versatile signaling factor that acts at ongoing forks and replication origins to determine the extent and quality of the cellular response to replication stress
  • CELLULAR PROCESS cell cycle, division, mitosis
    cell cycle, checkpoint
    PHYSIOLOGICAL PROCESS development
    text
  • cell proliferation control
  • gametogenesis
  • PATHWAY
    metabolism
    signaling
    a component
  • component of the G2/M checkpoint
  • component of the DNA damage and replication checkpoints
  • INTERACTION
    DNA
    RNA
    small molecule nucleotide,
  • ATP
  • protein
  • phosphorylating and inactivating CDC25C
  • mediating ATR, checkpoint inhibition of replication induction following UV induced DNA damage
  • interacting wih AURKB (phosphorylates Aurora-B and enhances its catalytic activity)
  • FBXO6 regulates CHEK1 stability and cellular sensitivity to replication stress
  • CLSPN acts synergistically with damaged DNA to increase phosphorylation of CHEK1 by ATR
  • interacting with FANCM (most likely contributes to CHEK1 and SMC1A phosphorylation by stimulating ATR activity towards its targets through promoting TOPBP1 retention on chromatin)
  • CLASPIN appears to be a master regulator of CHEK1 activity
  • CDC14B as a CHEK1 substrate (interplay between CHEK1 kinase and CDC14B phosphatase involving radiation-induced nucleolar shuttling to facilitate error-free cell cycle progression and prevent genomic instability)
  • CHEK1-mediated protection of replication forks from MUS81/EME1 even under otherwise unchallenged conditions is therefore vital to prevent uncontrolled fork collapse and ensure proper S-phase progression in human cells)
  • Claspin and RAD17 are reportedly involved in the DNA damage-induced phosphorylation of CHEK1, a hallmark of checkpoint activation
  • CHEK1 phosphorylation of SETMAR enhances DNA repair but inhibits replication fork restart
  • RPS6KA1 facilitates nuclear CHEK1 accumulation through CHEK1-Ser-280 phosphorylation and this pathway plays an important role in the preparation for monitoring genetic stability during cell proliferation
  • CHEK1 phosphorylates ERRFI1 on Ser 251, resulting in the inhibition of ERRFI1, and CHEK1 acts as a positive regulator of EGF signalling
  • CASP and non-CASP family proteases intricately regulate cleavage for up-regulation of CHEK1 kinase activity during programmed cell death
  • DTL targets the activated form of CHEK1 for destruction in the nucleoplasm rather than on chromatin and that this occurs in a PCNA-independent manner
  • WDR18 facilitates ATR-dependent CHEK1 phosphorylation via interacting with both C-terminus of TOPBP1 and CHEK1
  • NEK1 is required for efficient CHEK1 activation in human cells
  • TICRR stimulates ATR phosphorylation of CHEK1 in a TOPBP1-dependent manner
  • TLK1 and CHEK1 act in concert to modulate the phosphorylation status of RAD9A, which in turn serves to regulate the DNA damage response
  • CHEK1 is required for the metaphase-anaphase transition via regulating the subcellular localization and the expression of CDC20 and MAD2L1
  • SETMAR decreases CHEK1 interaction with DDB1, and decreases CHEK1 ubiquitination
  • function of HERC2/USP20 in coordinating CHEK1 activation by modulating CLSPN stability, which ultimately promotes genome stability and suppresses tumor growth
  • APOBEC3A expression caused ATR-dependent phosphorylation of CHEK1 and cell-cycle arrest, consistent with replication checkpoint activation
  • HUWE1 plays a significant role in the regulation of the DNA damage repair (DDR) signaling pathway by directly modulating the abundance of CHEK1 protein
  • cell & other
    REGULATION
    activated by BRCA1 upon DNA damage
    Other regulated (phosphorylated) by ATR
    phosphorylation by CDK1 participates in cytoplasmic sequestration of CHEK1 activity, which releases CDK1 inhibition in the nucleus and promotes mitotic entry
    unique regulatory mechanisms of CHEK1 phosphorylation and suggest that expression of constitutively active CHEK1 may represent a novel strategy to suppress tumor growth
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    unstable mutations in colon and endometrial tumors
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    identification of CHEK1-S as an endogenous inhibitor of CHEK1 may open new areas of research in cell cycle regulation, DNA damage response, and cancer therapy
    cancerhemopathy 
    its inhibition may represent an attractive therapeutic opportunity in AML (acute myeloid leukemia) with complex karyotype
    ANIMAL & CELL MODELS