Disease relevance of CHK1

• Temporal expression of the Candida albicans genes CHK1 and CSSK1, adherence, and morphogenesis in a model of reconstituted human esophageal epithelial candidiasis [1].
• A series of chk1 deletion mutants has poorly developed aerial hyphae, autolysis, and no conidia [2].

High impact information on CHK1

• The checkpoint kinase Chk1 is an important mediator of cell cycle arrest following DNA damage [3].
• The secondary structure and side chain interactions stabilize the activation loop of Chk1 and enable kinase activity without phosphorylation of the catalytic domain [3].
• The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation [3].
• We show by mutagenesis that Chk1 functions redundantly with the kinase Cds1 at the replication checkpoint and that both kinases phosphorylate Cdc25 on the same sites, which include serine residues at positions 99, 192 and 359 [4].
• Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms [5].

Biological context of CHK1

• Nevertheless, a partial defect in G2/M-phase arrest following treatment with ionizing radiation, but not UV radiation, is associated with deletion of CHK1 [6].
• In fission yeast and mammals, mitotic arrest in response to DNA damage requires inhibitory Cdk phosphorylation regulated by Chk1 [5].
• Unlike other checkpoint mutants, chk1 mutants were only mildly sensitive to DNA damage, indicating that checkpoint functions besides cell cycle arrest influence damage sensitivity [5].
• This study indicates that Chk1 is required for function of the DNA damage checkpoint in Saccharomyces cerevisiae but acts through a distinct mechanism maintaining the abundance of Pds1, an anaphase inhibitor [5].
• Here we find that the cyclic-AMP-dependent protein kinase (PKA) pathway supports Chk1 in the regulation of mitosis by targeting the mitotic inducer Cdc20 [7].

Anatomical context of CHK1

• The fact that such an effect remains detectable in cells synchronized with the microtubule inhibitor nocodazole prior to gamma irradiation implies the existence of a CHK1-dependent checkpoint in M phase [6].
• Three other genes that are up regulated encode a cell surface protein (FLO1), a mannosyl transferase (MNN4-4), and a putative two-component histidine kinase (CHK1) that regulates cell wall biosynthesis in C. albicans [8].
• On the basis of this tree topology, it is proposed that, at early stages of evolution, the eukaryotic cell cycle was not controlled by CDKs and that only a subset of extant kinases, notably the DNA damage checkpoint kinase Chk1p, were in place [9].
• Moreover, we show that Chk1 activity is not appreciably altered during maturation, being maintained at basal levels, and that C-terminal truncation mutants of Chk1 have very high kinase activities, strong abilities to inhibit maturation, and altered subcellular localization in oocytes [10].

Associations of CHK1 with chemical compounds

• Here we report that Chk1p has a role in the intra-S-phase checkpoint activated when yeast cells replicate their DNA in the presence of low concentrations of hydroxyurea (HU) [11].
• The role of the Candida albicans histidine kinase [CHK1) gene in the regulation of cell wall mannan and glucan biosynthesis [12].
• We have characterized and functionally determined the roles of both a histidine kinase protein (Chk1p) and a response regulator (Ssk1p) protein from Candida albicans [13].
• Scc2 shares a motif with Chk1 (kinase checkpoint protein), that comprises part of the serine/threonine protein kinase motif, including the active-site residue [14].
• Total alkali-soluble hexose from the cell wall of the chk1 mutant (strain CHK21) was significantly reduced [12].

Enzymatic interactions of CHK1

• Here, we show that Pds1 is phosphorylated at multiple sites in vivo in response to DNA damage by Chk1 [15].

Regulatory relationships of CHK1

• Yeast Chk1p kinase regulates the metaphase-to-anaphase transition in the DNA-damage checkpoint pathway via securin (Pds1p) phosphorylation [11].

Other interactions of CHK1

• Downstream checkpoint kinases Chk1 and Dun1 play no detectable role in either promoting degradation or inhibiting it [16].
• Following the detection of DNA damage, the checkpoint signal is transduced via the Mec1 kinase, which in turn activates two kinases, Rad53 and Chk1 that act in parallel pathways to bring about the cell cycle arrest [17].
• However, little was known about how Rad9 facilitates the activation of Chk1 [18].
• Loss of Chk1 partially restored cell-growth parameters in tpp1 apn1 rad1 yeast, but at the same time exacerbated chromosome instability [19].
• The new gene, CHK1, has a deduced amino acid sequence 90% identical to Pmk1 of the rice blast fungus Magnaporthe grisea and 59% identical to Fus3 of Saccharomyces cerevisiae [2].

References