DNA mismatch repair-dependent activation of c-Abl/p73α/GADD45α- mediated apoptosis

Shan Li Long, Julio C. Morales, Arlene Hwang, Mark W. Wagner, David A. Boothman

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Cells with functional DNA mismatch repair (MMR) stimulate G2 cell cycle checkpoint arrest and apoptosis in response to N-methyl-N′- nitro-N-nitrosoguanidine (MNNG). MMR-deficient cells fail to detect MNNG-induced DNA damage, resulting in the survival of "mutator" cells. The retrograde (nucleus-tocytoplasm) signaling that initiates MMR-dependent G 2 arrest and cell death remains undefined. Since MMR-dependent phosphorylation and stabilization of p53 were noted, we investigated its role(s) in G2 arrest and apoptosis. Loss of p53 function by E6 expression, dominant-negative p53, or stable p53 knockdown failed to prevent MMR-dependent G2 arrest, apoptosis, or lethality. MMR-dependent c-Abl-mediated p73α and GADD45α protein up-regulation after MNNG exposure prompted us to examine c-Abl/p73α/GADD45α signaling in cell death responses. STI571 (Gleevec™, a c-Abl tyrosine kinase inhibitor) and stable c-Abl, p73α, and GADD45α knockdown prevented MMR-dependent apoptosis. Interestingly, stable p73α knockdown blocked MMR-dependent apoptosis, but not G2 arrest, thereby uncoupling G2 arrest from lethality. Thus, MMR-dependent intrinsic apoptosis is p53-independent, but stimulated by hMLH1/c-Abl/p73α/GADD45α retrograde signaling.

Original languageEnglish (US)
Pages (from-to)21394-21403
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number31
DOIs
StatePublished - Aug 1 2008

Fingerprint

DNA Mismatch Repair
Repair
Chemical activation
Apoptosis
DNA
G2 Phase Cell Cycle Checkpoints
Nitrosoguanidines
Cell death
Cell Death
Methylnitronitrosoguanidine
Phosphorylation
Protein-Tyrosine Kinases
DNA Damage
Cell Survival
Up-Regulation
Stabilization
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

DNA mismatch repair-dependent activation of c-Abl/p73α/GADD45α- mediated apoptosis. / Long, Shan Li; Morales, Julio C.; Hwang, Arlene; Wagner, Mark W.; Boothman, David A.

In: Journal of Biological Chemistry, Vol. 283, No. 31, 01.08.2008, p. 21394-21403.

Research output: Contribution to journalArticle

Long, Shan Li ; Morales, Julio C. ; Hwang, Arlene ; Wagner, Mark W. ; Boothman, David A. / DNA mismatch repair-dependent activation of c-Abl/p73α/GADD45α- mediated apoptosis. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 31. pp. 21394-21403.
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