Heterozygous ATR mutations in mismatch repair-deficient cancer cells have functional significance

Kriste A. Lewis, Sally Mullany, Bijoy Thomas, Jeremy Chien, Ralitsa Loewen, Vijayalakshmi Shridhar, William Arthur Cliby

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39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7091-7095
Number of pages5
JournalCancer Research
Volume65
Issue number16
DOIs
StatePublished - Aug 15 2005

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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