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.
Checkpoint kinase 2 (Chk2) is emerging as a key mediator of diverse cellular responses to genotoxic stress, guarding the integrity of the genome throughout eukaryotic evolution. Recent studies show the fundamental role of Chk2 in the network of genome-surveillance pathways that coordinate cell-cycle progression with DNA repair and cell survival or death. Defects in Chk2 contribute to the development of both hereditary and sporadic human cancers, and earmark this kinase as a candidate tumour suppressor and an attractive target for drug discovery.
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- EPIGENETIC CHANGES
The alteration of gene expression through transcriptional (due to promoter methylation) or post-transcriptional mechanisms, rather than 'genetic' alteration of sequences of bases in genomic DNA.
- RADIOMIMETIC DRUGS
Drugs that have cellular effects that are similar to those of ionizing radiation, such as the induction of double-stranded DNA breaks.
- ACTIVATION LOOP
A conserved structural motif in kinase domains, which needs to be phosphorylated for full activation of the kinase.
- SRC HOMOLOGY-3 (SH3) DOMAIN
A non-catalytic homology region which mediates protein?protein interactions and was first identified in Src-related protein kinases. SH3 domains bind to proline (Pro)-rich peptides that contain the minimal consensus Pro?X?X?Pro (in which X is any amino acid).
A checkpoint regulator and tumour suppressor, which is mutated with high incidence in human breast and ovarian cancers.
- BRCT HOMOLOGY DOMAIN
An evolutionarily conserved protein?protein interaction domain, first described in the carboxy-terminal part of the BRCA1 tumour suppressor (BRCT; BRCA1 carboxy terminal), and subsequently identified in other checkpoint proteins.
- HOMOLOGOUS RECOMBINATIONAL REPAIR
A mechanism for the repair of double-stranded DNA breaks, which relies on the presence of the homologous, intact DNA partner as a template.
- TRANSCRIPTION-COUPLED REPAIR
Preferential removal of lesions from the DNA strands in genes that are actively transcribed by RNA polymerase II.
- CHROMATIN REMODELLING
Dynamic changes of chromatin organization, which are required for optimal execution of processes such as DNA replication, gene transcription, DNA repair or chromosome segregation.
- 14-3-3 PROTEINS
An evolutionarily conserved group of regulatory proteins that bind to discrete phosphoserine-containing motifs. 14-3-3 proteins seem to sequester their binding partners and, in some cases, actively export them to the cytoplasm.
- ORIGINS OF DNA REPLICATION
Sites on chromosomal DNA where replicative DNA synthesis is initiated. In some organisms, such as yeast, the origins of replication are defined by a specific DNA sequence.
- SPERMATOGONIA AND SPERMATOCYTES
Successive developmental stages of male germ-cell maturation. Mitotically proliferating spermatogonia mature into spermatocytes, which undergo meiotic divisions, followed by functional maturation into spermatids and spermatozoa.
- LI?FRAUMENI SYNDROME
A highly cancer-prone familial disorder (clinically defined by Li and Fraumeni in 1988), that is caused by germline mutations in TP53 or other tumour-suppressor genes, including CHK2.
- E2F TRANSCRIPTION FACTORS
A family of six proteins that regulate expression of genes that are required for DNA replication.
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Bartek, J., Falck, J. & Lukas, J. Chk2 kinase — a busy messenger. Nat Rev Mol Cell Biol 2, 877–886 (2001). https://doi.org/10.1038/35103059
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