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hMutSalpha- and hMutLalpha-dependent phosphorylation of p53 in response to DNA methylator damage.

Publication ,  Journal Article
Duckett, DR; Bronstein, SM; Taya, Y; Modrich, P
Published in: Proc Natl Acad Sci U S A
October 26, 1999

hMSH2.hMSH6 heterodimer (hMutSalpha) and hMLH1.hPMS2 complex (hMutLalpha) have been implicated in the cytotoxic response of mammalian cells to a number of DNA-damaging compounds, including methylating agents that produce O(6)-methylguanine (O(6)MeG) adducts. This study demonstrates that O(6)MeG lesions, in which the damaged base is paired with either T or C, are subject to excision repair in a reaction that depends on a functional mismatch repair system. Furthermore, treatment of human cells with the S(N)1 DNA methylators N-methyl-N-nitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine results in p53 phosphorylation on serine residues 15 and 392, and these phosphorylation events depend on the presence of functional hMutSalpha and hMutLalpha. Coupled with the previous demonstration that O(6)MeG.T and O(6)MeG.C pairs are recognized by hMutSalpha, these results implicate action of the mismatch repair system in the initial step of a damage-signaling cascade that can lead to cell-cycle checkpoint activation or cell death in response to DNA methylator damage.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

October 26, 1999

Volume

96

Issue

22

Start / End Page

12384 / 12388

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Saccharomyces cerevisiae Proteins
  • Phosphorylation
  • MutS DNA Mismatch-Binding Protein
  • MutL Proteins
  • Humans
  • Fungal Proteins
  • Escherichia coli Proteins
  • DNA-Binding Proteins
  • DNA Primers
 

Citation

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Duckett, D. R., Bronstein, S. M., Taya, Y., & Modrich, P. (1999). hMutSalpha- and hMutLalpha-dependent phosphorylation of p53 in response to DNA methylator damage. Proc Natl Acad Sci U S A, 96(22), 12384–12388. https://doi.org/10.1073/pnas.96.22.12384
Duckett, D. R., S. M. Bronstein, Y. Taya, and P. Modrich. “hMutSalpha- and hMutLalpha-dependent phosphorylation of p53 in response to DNA methylator damage.Proc Natl Acad Sci U S A 96, no. 22 (October 26, 1999): 12384–88. https://doi.org/10.1073/pnas.96.22.12384.
Duckett DR, Bronstein SM, Taya Y, Modrich P. hMutSalpha- and hMutLalpha-dependent phosphorylation of p53 in response to DNA methylator damage. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12384–8.
Duckett, D. R., et al. “hMutSalpha- and hMutLalpha-dependent phosphorylation of p53 in response to DNA methylator damage.Proc Natl Acad Sci U S A, vol. 96, no. 22, Oct. 1999, pp. 12384–88. Pubmed, doi:10.1073/pnas.96.22.12384.
Duckett DR, Bronstein SM, Taya Y, Modrich P. hMutSalpha- and hMutLalpha-dependent phosphorylation of p53 in response to DNA methylator damage. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12384–12388.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

October 26, 1999

Volume

96

Issue

22

Start / End Page

12384 / 12388

Location

United States

Related Subject Headings

  • Tumor Suppressor Protein p53
  • Saccharomyces cerevisiae Proteins
  • Phosphorylation
  • MutS DNA Mismatch-Binding Protein
  • MutL Proteins
  • Humans
  • Fungal Proteins
  • Escherichia coli Proteins
  • DNA-Binding Proteins
  • DNA Primers