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[Cancer Research 65, 7091-7095, August 15, 2005]
© 2005 American Association for Cancer Research

Priority Reports

Heterozygous ATR Mutations in Mismatch Repair–Deficient Cancer Cells Have Functional Significance

Kriste A. Lewis1, Sally Mullany1, Bijoy Thomas1, Jeremy Chien2, Ralitsa Loewen1, Viji Shridhar2 and William A. Cliby1

Departments of 1 Obstetrics and Gynecology and 2 Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota

Requests for reprints: William A. Cliby, Department of Obstetrics and Gynecology, Mayo Clinic and Foundation, 1317 Guggenheim, 200 1st Street, Southwest Rochester, MN 55905. Phone: 507-266-9323; Fax: 507-266-9300; E-mail: Cliby.william{at}mayo.edu.

ATR (ataxia telangiectasia and Rad3-related) function is necessary for the proper response to commonly used chemotherapeutic agents. Heterozygous truncating mutations in exon 10 of the ATR gene have been described in numerous cancers exhibiting microsatellite instability. We show that truncating mutations of ATR are capable of acting in a dominant-negative manner to abrogate ATR-dependent Chk1 phosphorylation and cell-cycle arrests after DNA damage. In addition, endometrial cell lines harboring ATR mutations are defective for ATR-dependent responses. These findings imply that ATR mutations play an important role in the development and clinical behavior of a subset of microsatellite instability–positive endometrial, colon, and stomach cancers.




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Molecular Cancer Research Cancer Prevention Research
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Copyright © 2005 by the American Association for Cancer Research.