The interplay between hMLH1 and hMRE11: Role in MMR and the effect of hMLH1 mutations

Nianxi Zhao, Fengxue Zhu, Fenghua Yuan, Anoria K. Haick, Shinichi Fukushige, Liya Gu, Chengtao Her

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Our previous studies indicate that hMRE11 plays a role in MMR, and this function of hMRE11 is most likely mediated by the hMLH1-hMRE11 interaction. Here, we explored the functional implications of the hMLH1-hMRE11 interaction in MMR and the effects of hMLH1 mutations on their interaction. Our in vitro MMR assay demonstrated that the dominant-negative hMRE11452-634 mutant peptide (i.e., harboring only the hMLH1-interacting domain) imparted a significant reduction in both 3′ excision and 3′-directed MMR activities. Furthermore, the expression of hMRE11452-634, and to a lesser extent hMRE111-634 (ATLD1), impaired G2/M checkpoint control in response to MNU and cisplatin treatments, rendering cells resistant to killings by these two anticancer drugs. Analysis of 38 hMLH1 missense mutations showed that the majority of mutations caused significant (>50%) reductions in their interaction with hMRE11, suggesting a potential link between aberrant protein interaction and the pathogenic effects of hMLH1 variants.

Original languageEnglish (US)
Pages (from-to)338-343
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume370
Issue number2
DOIs
StatePublished - May 30 2008

Keywords

  • Cisplatin
  • G2/M checkpoint
  • MMR
  • MNU
  • hMLH1
  • hMRE11

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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