Chk2 kinase — a busy messenger

Abstract

To protect genome integrity, eukaryotic cells possess evolutionarily conserved surveillance mechanisms that are termed checkpoints, which constantly monitor the status and quality of chromosomal DNA and delay cell-cycle progression in response to replication stress or various types of DNA damage. The recent cloning of mammalian Chk2, a protein kinase that is homologous to yeast Rad53/cds1, has sparked an avalanche of exciting research, which shows the essential role of Chk2 in transmitting checkpoint signals from upstream detectors of DNA lesions to cell-cycle effectors and the DNA-repair machinery. The overall structure of Chk2 is remarkably conserved throughout evolution, which is consistent with its involvement in cellular processes of general importance. Phosphorylation of the amino-terminal regulatory region of Chk2 by the upstream ATM/ATR kinases, autophosphorylation within the carboxy-terminal kinase domain, and protein?protein interactions that are mediated by the central forkhead-associated (FHA) domain showed exciting insights into the complexity of molecular events during the early cellular response to genotoxic stress. The growing number of Chk2 targets include the cell-cycle-regulating Cdc25A and Cdc25C phosphatases, and the tumour suppressors p53 and BRCA1. By phosphorylating these (and presumably other) effector proteins, Chk2 links the early checkpoint events with cell-cycle arrest in the G1, S and G2 phases, activation of DNA repair or, in some cases, programmed cell death. Analysis of different human tissues using newly developed antibodies showed an unexpected correlation of Chk2 expression with tissue biology, which indicates that as well as guarding against genetic instability in proliferating cells, Chk2 might also have an important function in propagating DNA-damage signals in quiescent and/or differentiated tissues. The identification of Chk2 mutations in different human cancer types and the subsequent biochemical analyses of the tumour-associated Chk2 alleles qualify Chk2 as a novel tumour suppressor and open up unprecedented possibilities in the search for a new generation of drugs for cancer therapy.