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CHK2 kinase: cancer susceptibility and cancer therapy – two sides of the same coin?

Key Points

  • CHK2 is a versatile and multifunctional kinase that regulates the cell's response to DNA damage by phosphorylating a number of distinct cellular substrates.

  • CHK2 can prevent tumour progression by averting genomic instability through DNA repair and, if this is not possible, by causing the cell to senesce or die.

  • Human genetic studies clearly show that CHEK2 is a multiorgan tumour susceptibility gene, but current evidence indicates that CHEK2 on its own does not predispose to cancer.

  • A potential therapeutic approach in patients whose tumours harbour CHEK2 mutations may be treatment with inhibitors of other proteins that are involved in DNA-repair pathways, inactivation of which may be lethal in combination with a loss of CHEK2.

  • Looking at the other side of the coin, in cancer patients with a functional CHK2 protein a key issue is defining how this kinase manages to elicit distinct cellular outcomes such as cell survival through DNA repair versus apoptosis or senescence.

Abstract

In the past decade, CHK2 has emerged as an important multifunctional player in the DNA-damage response signalling pathway. Parallel studies of the human CHEK2 gene have also highlighted its role as a candidate multiorgan tumour susceptibility gene rather than a highly penetrant predisposition gene for Li–Fraumeni syndrome. As discussed here, our current understanding of CHK2 function in tumour cells, in both a biological and genetic context, suggests that targeted modulation of the active kinase or exploitation of its loss in tumours could prove to be effective anti-cancer strategies.

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Figure 1: Schematic overview of the DNA-damage response signalling pathway.
Figure 2: Structure and activation of human CHK2 protein.

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Acknowledgements

We would like to apologise to all those researchers whose studies have not been cited because of space limitations. We would like to thank A. Oliver and L. Pearl for providing Fig 2b.

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Correspondence to Michelle D. Garrett.

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Ian Collins' laboratories have received funding from Astex Therapeutics Ltd and Vernalis Ltd and have participated in collaborative research with Sareum Ltd and Cancer Research Technologies Ltd. Michelle D. Garrett's laboratories have received funding from Astex Therapeutics and have participated in collaborative research with Sarum Ltd and Cancer Research Technologies.

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Glossary

Cell-cycle checkpoint

A molecular check in the cell cycle to prevent initiation of the next phase in case the DNA is damaged or another condition endangers accurate and safe cell division.

Li–Fraumeni Syndrome

(LFS). A rare syndrome characterized by a familial cluster of very early onset cancers at multiple sites, including sarcoma, breast, brain and adrenocortical tumours. Definition of a classical LFS family: a sarcoma at <45 years, one first-degree relative with cancer at <45 years and one first- or second-degree relative in the same lineage with cancer at <45 years.

Non-homologous end joining repair

(NHEJ). Unlike homologous recombination repair, NHEJ rejoins broken ends of DNA following double-strand breaks without using a homologous DNA template and can therefore be accompanied by loss of nucleotides and errors.

Base-excision repair

(BER). BER replaces non-bulky damage of single bases that have been altered by alkylation, oxidation or deamination.

14-3-3

A group of proteins that bind to phospho-proteins and regulate their action mainly by controlling their subcellular localization.

Therapeutic index

Comparison of the amount of a therapeutic agent that has the desired effect with the amount that causes toxic or side effects.

E2F

Family of transcription factors that regulate the expression of genes implicated in cell-cycle progression and apoptosis, and whose activity is repressed by the retinoblastoma (pRb) tumour suppressor.

Mitotic catastrophe

Another form of cell death that occurs during or just after mitosis and is characterized by micronuclei or multi-nuclei.

Penetrance

The likelihood a given gene present in the germ line of an organism will result in disease.

Loss of heterozygosity

Classical tumour-suppressor genes are considered to be recessive. Thus, cells that contain one normal and one mutated form of a tumour-suppressor gene in the germ line are functionally normal. The condition that results in the loss of the remaining normal allele is known as loss of heterozygosity.

Dominant negative

A dominant-negative mutation occurs when the mutated gene product adversely affects the normal, wild-type gene product within the same cell.

Pseudogene

A defective copy of all the sequence of a functional gene or of portions of it.

Founder mutation

A founder mutation is a mutation in the germline DNA of one or more individuals who are founders of a distinct population.

First-degree relative

A first-degree relative is one of the following: a parent, a sibling or a child.

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Antoni, L., Sodha, N., Collins, I. et al. CHK2 kinase: cancer susceptibility and cancer therapy – two sides of the same coin?. Nat Rev Cancer 7, 925–936 (2007). https://doi.org/10.1038/nrc2251

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