Fission yeast chkl protein kinase links the rad checkpoint pathway to cdc2

Abstract

The dependence of cell-cycle progression on the integrity of the genome has been described as checkpoint control. A number of mutants of the fission yeast Schizosaccharomyces pombe, selected for their sensitivity to DNA damage caused by radiation (rad mutants) or to the DNA synthesis inhibitor hydroxyurea (hus mutants) have been classified as checkpoint mutants because they fail to arrest the cell cycle in response to DNA damage or incompletely replicated DNA. Coupling of the checkpoint pathways that monitor DNA repair and replication to control of the cell cycle is essential. In a search for components that interact with the cell-cycle regulatory kinase p34cdc2, we have identified a novel fission yeast protein kinase homologue which is involved in cell-cycle arrest when DNA damage has occurred or when unligated DNA is present. We have called the gene encoding this protein chk1 for checkpoint kinase. Multiple copies of chk1 partially rescue the ultraviolet sensitivity of rad1-1, a mutant deficient in checkpoint control. Identification of a gene involved in checkpoint control as a rescue of a cdc2 mutant links the rad1-dependent DNA-damage-sensing pathway and p34cdc2 activity.

Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells

“…This is unlikely to be the case since equal amounts of hchk1 protein were detected in AT1ABR and C3ABR but there is a defect in activation of chk1 in AT1ABR cells (Khanna et al, unpublished). Previous data demonstrate that a gainof-function caused by overexpression of chk1 alone in S. pombe acting downstream of the ATM homologue rad3, leads to G2 arrest (Al-Khodairy et al, 1994;Ford et al, 1994;Walworth et al, 1993). In addition moderate overexpression of chk1 in S. pombe rad mutants, at levels that do not e ect mitotic entry, restored partially their level of survival after DNA damage (Walworth et al, 1993).…”

Mitotic DNA damage and replication checkpoints in yeast

“…Cells with the chk1 sp Δ mutation are not as sensitive to DNA damage as cells with a deletion of any of the checkpoint rad genes, suggesting that the checkpoint Rad proteins also have a Chk1 sp independent role, perhaps in activating DNA repair [14,30]. Furthermore, deletion of Chk1 sp does not affect the S/M checkpoint, indicating that the checkpoint rad genes have other targets in the S/M checkpoint, as discussed below [14,30]. Chk1 sp is phosphorylated in response to DNA damage and this phosphorylation depends on the checkpoint Rad proteins [31].…”

“…Specifically, Chk1 sp is not phosphorylated in response to HU [31]. While this does not necessarily mean that Chk1 sp is not activated by HU, Chk1 sp is not normally required for an HU induced arrest [14,30]. Instead, the protein kinase Cds1 sp plays the analogous role in the S/M checkpoint [73••,74••,75].…”

Resposta a danos no DNA após exposição à luz ultravioleta: apagando o fogo antes do incêndio celular

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