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| Subject Categories: Cell Cycle | Genome Stability & Dynamics |
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| The EMBO Journal
(2003) 22, 713–723, doi:10.1093/emboj/cdg060 |
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| Chk1-deficient tumour cells are viable but exhibit multiple checkpoint and survival defects |
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| George Zachos1, Michael D. Rainey1 and David A.F. Gillespie2 |
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1 Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow G61 1BD UK 2 Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK To whom correspondence should be addressed David A.F. Gillespie, d.gillespie@beatson.gla.ac.uk Received 17 September 2002; Revised 28 November 2002; Accepted 4 December 2002. |
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| Abstract |
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| The conserved protein kinase Chk1 is believed to play an important role in checkpoint responses to aberrant DNA structures; however, genetic analysis of Chk1 functions in metazoans is complicated by lethality of Chk1-deficient embryonic cells. We have used gene targeting to eliminate Chk1 function in somatic DT40 B-lymphoma cells. We find that Chk1-deficient DT40 cells are viable, but fail to arrest in G2/M in response to and are hypersensitive to killing by ionizing radiation. Chk1-deficient cells also fail to maintain viable replication forks or suppress futile origin firing when DNA polymerase is inhibited, leading to incomplete genome duplication and diminished cell survival after release from replication arrest. In contrast to embryonic cells, however, Chk1 is not required to delay mitosis when DNA synthesis is inhibited. Thus, Chk1 is dispensable for normal cell division in somatic DT40 cells but is essential for DNA damage-induced G2/M arrest and a subset of replication checkpoint responses. Furthermore, Chk1-dependent processes promote tumour cell survival after perturbations of DNA structure or metabolism. |
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| Keywords: cell survival, checkpoints, Chk1, DNA damage, DNA replication |
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