Apoptosis and mutation in the murine small intestine

Loss of Mlh1- and Pms2-dependent apoptosis leads to increased mutation in vivo

Owen J. Sansom, Stefan M. Bishop, Helen Court, Sandra Dudley, Robert (Mike) Liskay, Alan R. Clarke

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The mismatch repair (MMR) protein Msh2 has been shown to function in the apoptotic response to alkylating agents in vivo. Here, we extend these studies to the MutL homologues (MLH) Mlh1 and Pms2 by analysing the apoptotic response within the small intestine of gene targeted strains. We demonstrate significant differences between Msh2, Mlh1 and Pms2 mutations in influencing apoptotic signalling following 50mg/kg N-methyl-nitrosourea (NMNU), with no obvious reliance upon either Mlh1 or Pms2. However, following exposure to 100mg/kg temozolomide or lower levels of NMNU (10mg/kg) both Mlh1- and Pms2-dependent apoptosis was observed, indicating that the apoptotic response at these levels of DNA damage is dependent on the MutL homologues. Given our ability to observe a MutLα dependence of the apoptotic response, we tested whether perturbations of this response directly translate into increases in mutation frequency in vivo. We show that treatment with temozolomide or 10mg/kg NMNU significantly increases mutation in both the Mlh1 and Pms2 mutant mice. At higher levels of NMNU, where the apoptotic response is independent of Mlh1 and Pms2, no gene dependent increase in mutation frequency was observed. These results argue that the MutSα and MutLα are not equally important in their ability to signal apoptosis. However, when MMR does mediate apoptosis, perturbation of this response leads to long-term persistence of mutant cells in vivo.

Original languageEnglish (US)
Pages (from-to)1029-1039
Number of pages11
JournalDNA Repair
Volume2
Issue number9
DOIs
StatePublished - Sep 18 2003

Fingerprint

temozolomide
Small Intestine
DNA Mismatch Repair
Mutation Rate
Apoptosis
Mutation
Repair
Genes
Alkylating Agents
DNA Damage
DNA
Proteins
MutL Proteins

Keywords

  • Apoptosis
  • Methylation
  • Mismatch repair
  • p53

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Apoptosis and mutation in the murine small intestine : Loss of Mlh1- and Pms2-dependent apoptosis leads to increased mutation in vivo. / Sansom, Owen J.; Bishop, Stefan M.; Court, Helen; Dudley, Sandra; Liskay, Robert (Mike); Clarke, Alan R.

In: DNA Repair, Vol. 2, No. 9, 18.09.2003, p. 1029-1039.

Research output: Contribution to journalArticle

Sansom, Owen J. ; Bishop, Stefan M. ; Court, Helen ; Dudley, Sandra ; Liskay, Robert (Mike) ; Clarke, Alan R. / Apoptosis and mutation in the murine small intestine : Loss of Mlh1- and Pms2-dependent apoptosis leads to increased mutation in vivo. In: DNA Repair. 2003 ; Vol. 2, No. 9. pp. 1029-1039.
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