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Overexpression of a kinase‐inactive ATR protein causes sensitivity to DNA‐damaging agents and defects in cell cycle checkpoints
Author(s) -
Cliby William A.,
Roberts Christopher J.,
Cimprich Karlene A.,
Stringer Cheri M.,
Lamb John R.,
Schreiber Stuart L.,
Friend Stephen H.
Publication year - 1998
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/17.1.159
Subject(s) - biology , dna damage , dna repair , chek1 , radioresistance , kinase , methyl methanesulfonate , radiation sensitivity , cell cycle , ataxia telangiectasia , dna pkcs , microbiology and biotechnology , mitosis , g2 m dna damage checkpoint , dna replication , dna , mutation , cell cycle checkpoint , biochemistry , cell , genetics , cell culture , gene , irradiation , physics , nuclear physics
ATR, a phosphatidylinositol kinase‐related protein homologous to ataxia telangiectasia mutated (ATM), is important for the survival of human cells following many forms of DNA damage. Expression of a kinase‐inactive allele of ATR (ATRkd) in human fibroblasts causes increased sensitivity to ionizing radiation (IR), cis ‐platinum and methyl methanesulfonate, but only slight UV radiation sensitivity. ATRkd overexpression abrogates the G 2 /M arrest after exposure to IR, and overexpression of wild‐type ATR complements the radioresistant DNA synthesis phenotype of cells lacking ATM, suggesting a potential functional overlap between these proteins. ATRkd overexpression also causes increased sensitivity to hydroxyurea that is associated with microtubule‐mediated nuclear abnormalities. These observations are consistent with uncoupling of certain mitotic events from the completion of S‐phase. Thus, ATR is an important component of multiple DNA damage response pathways and may be involved in the DNA replication (S/M) checkpoint.