Role of c-Abl kinase in DNA mismatch repair-dependent G2 cell cycle checkpoint arrest responses

Mark W. Wagner, Shan Li Long, Julio C. Morales, Cristi L. Galindo, Harold R. Garner, William G. Bornmann, David A. Boothman

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Current published data suggest that DNA mismatch repair (MMR) triggers prolonged G2 cell cycle checkpoint arrest after alkylation damage from N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) by activating ATR (ataxia telangiectasia-Rad3-related kinase). However, analyses of isogenic MMR-proficient and MMR-deficient human RKO colon cancer cells revealed that although ATR/Chk1 signaling controlled G2 arrest in MMR-deficient cells, ATR/Chk1 activation was not involved in MMR-dependent G2 arrest. Instead, we discovered that disrupting c-Abl activity using STI571 (Gleevec™, a c-Abl inhibitor) or stable c-Abl knockdown abolished MMR-dependent p73α stabilization, induction of GADD45α protein expression, and G2 arrest. In addition, inhibition of c-Abl also increased the survival of MNNG-exposed MMR-proficient cells to a level comparable with MMR-deficient cells. Furthermore, knocking down GADD45α (but not p73α) protein levels affected MMR-dependent G2 arrest responses. Thus, MMR-dependent G2 arrest responses triggered by MNNG are dependent on a human MLH1/c-Abl/GADD45α signaling pathway and activity. Furthermore, our data suggest that caution should be taken with therapies targeting c-Abl kinase because increased survival of mutator phenotypes may be an unwanted consequence.

Original languageEnglish (US)
Pages (from-to)21382-21393
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number31
DOIs
StatePublished - Aug 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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