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Chk1‐deficient tumour cells are viable but exhibit multiple checkpoint and survival defects
Author(s) -
Zachos George,
Rainey Michael D.,
Gillespie David A.F.
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg060
Subject(s) - biology , chek1 , g2 m dna damage checkpoint , mitosis , microbiology and biotechnology , dna damage , somatic cell , dna replication , cell cycle checkpoint , mitotic catastrophe , dna repair , cell cycle , dna , genetics , cancer research , gene
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 G 2 /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 G 2 /M arrest and a subset of replication checkpoint responses. Furthermore, Chk1‐dependent processes promote tumour cell survival after perturbations of DNA structure or metabolism.