checkpoint kinase 1; serine/threonine protein kinase Chk1 (CHEK1, CHK1)

Function

• required for checkpoint mediated cell cycle arrest in response to DNA damage or the presence of unreplicated DNA
• may also negatively regulate cell cycle progression during unperturbed cell cycles
• recognizes the substrate consensus sequence [R-X-X-S/T]
• binds to & phosphorylates CDC25A, CDC25B & CDC25C
• phosphorylation of CDC25A at Ser-178 & Thr-507 & phosphorylation of CDC25C at Ser-216 creates binding sites for 14-3-3 proteins which inhibit CDC25A & CDC25C
• phosphorylation of CDC25A at Ser-76, Ser-124, Ser-178, Ser-279 & Ser-293 promotes proteolysis of CDC25A
• inhibition of CDC25 activity leads to increased inhibitory Tyr phosphorylation of CDK-cyclin complexes & blocks cell cycle progression
• inhibition of CDC25C prevents activation of CDC2-cyclin B complex & mitotic entry
• binds to & phosphorylates RAD51 at Thr-309, which may enhance the association of RAD51 with chromatin & promote DNA repair by homologous recombination
• binds to & phosphorylates TLK1 at Ser-743, which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A
• this may affect chromatin assembly during S phase or DNA repair
• may also phosphorylate multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation & enhances suppression of cellular proliferation
• interacts with BRCA1, CLSPN, PPM1D, RAD51, TIMELESS, XPO1/CRM1 & YWHAZ/14-3-3 zeta
• phosphorylated by ATR (RAD17-dependent) in response to ultraviolet irradiation & inhibition of DNA replication
• phosphorylated by ATM in response to ionizing irradiation
• ATM & ATR can both phosphorylate Ser-317 & Ser-345; this phosphorylaton results in enhanced kinase activity
• phosphorylation at Ser-345 also increases binding to 14-3-3 proteins & promotes nuclear retention.
• conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest
• may also be phosphorylated at Ser-280 by AKT1/PKB, which may promote mono &/or diubiquitination
• also phosphorylated at undefined residues during mitotic arrest, which results in decreased activity
• ubiquitinated
• mono or diubiquitination promotes nuclear exclusion (putative)

Structure

• autoinhibitory region (AIR) inhibits the activity of the kinase domain
• belongs to the protein kinase superfamily, CAMK Ser/Thr protein kinase family, NIM1 subfamily
• contains 1 protein kinase domain

Compartment

• nucleus, cytoplasm
• 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

Expression

• expressed ubiquitously
• most abundant expression in thymus, testis, small intestine & colon

More general terms

• checkpoint kinase

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1111
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:1111
• OMIM: https://mirror.omim.org/entry/603078
• UniProt: http://www.uniprot.org/uniprot/O14757.html