Chk1

CHK1 contains 1 protein kinase domain and belongs to the protein kinase superfamily, CAMK Ser/Thr protein kinase family, NIM1 subfamily. It is a member of checkpoint kinases (Chks). Chks Checkpoint kinases (Chks) are serine/threonine kinases that are involved in the control of the cell cycle. There are two subtypes of chks that have so far been identified, Chk1 and Chk2. They are essential components to delay cell cycle progression in normal and damaged cells and can act at all three cell cycle checkpoints. Chks are activated by phosphorylation. ATR kinase phosphorylates Chk1 in response to single strand DNA breaks and ATM kinase phosphorylates Chk2 in response to double strand breaks. Chks phosphorylate Cdc25 phosphatase at Ser216, which leads to Cdc25 sequestration in the cytoplasm. Chks have a role in the physiological stress of hypoxia/reoxygenation. CHK1 is required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA. CHK1 may also negatively regulate cell cycle progression during unperturbed cell cycles.

Chk1 Related Areas

Cancer>>Cell Cycle >>DNA Repair>> CHK1

Chk1 Alternative Names

CHK1 checkpoint homolog, Cell cycle checkpoint kinase, Checkpoint kinase-1 [Homo sapiens]

CHK1 checkpoint homolog, Checkpoint kinase-1 [Mus musculus]

Summaries for Chk1

Entrez Gene summary for Chk1:

The protein encoded by this gene belongs to the Ser/Thr protein kinase family. It is required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA. This protein acts to integrate signals from ATM and ATR, two cell cycle proteins involved in DNA damage responses, that also associate with chromatin in meiotic prophase I. Phosphorylation of CDC25A protein phosphatase by this protein is required for cells to delay cell cycle progression in response to double-strand DNA breaks. Several alternatively spliced transcript variants have been found for this gene

OMIM - description for Chk1:

Checkpoint pathways control the order and timing of cell cycle transitions and ensure that critical events, such as DNA replication and chromosome segregation, are completed with high fidelity. The S. pombe Chk1 gene encodes a protein kinase that is required for the DNA damage checkpoint. Both Sanchez et al. (1997) and Flaggs et al. (1997) identified mouse and human homologs of Chk1. Flaggs et al. (1997) stated that the predicted proteins share 90% sequence identity through the protein kinase domains. Sanchez et al. (1997) reported that the sequence of the predicted 476-amino acid human CHK1 protein is 29%, 40%, and 44% identical to those of the fission yeast Chk1, C. elegans Chk1, and Drosophila 'grapes' (grp) proteins, respectively. Northern blot analysis revealed that CHK1 is expressed ubiquitously as an approximately 2.4-kb mRNA, with the most abundant expression in thymus, testis, small intestine, and colon. Antibodies against CHK1 recognized a 54-kD protein on immunoblots of mammalian cell extracts. However, the protein had altered mobility when isolated from cells treated with ionizing radiation (IR), indicating that CHK1 is modified in response to DNA damage. In vitro, CHK1 directly phosphorylated a regulator of CDC2 (116940) tyrosine phosphorylation, CDC25C (157680). The authors proposed that, in response to DNA damage, CHK1 phosphorylates and inhibits CDC25C, thus preventing activation of the CDC2-cyclin B complex and mitotic entry.

Wikipedia summary for Chk1:

Serine/threonine-protein kinase Chk1 is an enzyme that in humans is encoded by the CHEK1 gene.[2][3] Chk1 is a kinase that phosphorylates cdc25, an important phosphatase in cell cycle control, particularly for entry into mitosis. Cdc25, when phosphorylated on serine 216 by chk1 becomes bound by an adaptor protein in the cytoplasm. Therefore it is inhibited from removing the inhibiting phosphate from MPF (mitotic/maturation promoting factor) added by Wee1. Consequently, a cell is prevented from entering mitosis.

Human Chk1 Protein General Information

 

• Protein names: Recommended name: Serine/threonine-protein kinase Chk1
• Sequence length: 476 AA.
• Domain: The autoinhibitory region (AIR) inhibits the activity of the kinase domain.
• Sequence similarities: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily. Contains 1 protein kinase domain.
• Post-translational modification: Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity
• Subunit structure: Interacts (phosphorylated by ATR) with RAD51. Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1. Interacts with BRCA1. Interacts with and phosphorylates CDC25A, CDC25B and CDC25C. Interacts with FBXO6, which regulates CHEK1. Interacts with PPM1D, which regulates CHEK1 through dephosphorylation. Interacts with TIMELESS; DNA damage-dependent. Interacts with FEM1B; activates CHEK1 in response to stress. Interacts with TLK1. Interacts with XPO1 and YWHAZ.
• Subcellular location: Nucleus. Cytoplasm. Cytoplasm › cytoskeleton › centrosome. Note: Nuclear export is mediated at least in part by XPO1/CRM1. Also localizes to the centrosome specifically during interphase, where it may protect centrosomal CDC2 kinase from inappropriate activation by cytoplasmic CDC25B.
• Tissue specificity: Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.

General information above from UniProt

Function for Chk1 Protein

UniProtKB:

Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest

Genatlas:

• histone H3 kinase that regulates transcriptional repression in response to DNA damage
• Chk1 is required for cell cycle arrest in reponse to DNA damage, in association with 14.3.3 proteins (YWHA*)
• Chk1 is involved in negative regulation of cell proliferation
• activates FANC/BRCA pathway through FANCD2 monoubiquitination
• Chk1 acts as an integrator for Atm and Atr signals and may be involved in monitoring the processing of meiotic recombination
• Chk1 plays a role in regulating claspin stability in the cell
• Chk1 protects vertebrate cells against spontaneous chromosome missegregation and is required to sustain anaphase delay when spindle function is disrupted by taxol
• Chk1 could protect against tumorigenesis through its role in spindle checkpoint signaling
• Chk1 regulates the ubiquitination of PCNA with the help of claspin and timeless proteins
• Chk1 0activates NEK11 via phosphorylation on ser273
• Chk1 may promotes replication fork progression during normal S phase by controlling replication origin activity
• Chk1 roles 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

Homology for human Chk1

• homolog to yeast S.pombe rad3
• homolog to murine Chek1

Phenotype Information for Chk1

Phenotype Information for Chk1 from OMIM (Online Mendelian Inheritance in Man)

Drugs for Chk1

Target	Drug Name	Disease	Drug Status
Chk1	UCN-01	Non-Small Cell Lung Carcinoma	Phase II
Chk1	XL844	Advanced solid tumours or lymphoma	Suspended in Phase I
Chk1	AZD7762	Solid tumours; Advanced Solid Malignancies	Phase I
Chk1	7-hydroxystaurosporine	Leukaemia and MDS; solid tumours; lymphoma and solid tumours	Phase I
Chk1	7-hydroxystaurosporine	RCC, melanoma and lymphoma; SCLC	Phase II
Chk1	PF-477736	Advanced solid tumours in combination with gemcitabine	Phase I

Drugs for Chk1 from TTD (Therapeutic Targets Database)