Mutations affecting a putative MutLα endonuclease motif impact multiple mismatch repair functions

Naz Erdeniz, Megan Nguyen, Suzanne M. Deschênes, Robert (Mike) Liskay

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Mutations in DNA mismatch repair (MMR) lead to increased mutation rates and higher recombination between similar, but not identical sequences, as well as resistance to certain DNA methylating agents. Recently, a component of human MMR machinery, MutLα, has been shown to display a latent endonuclease activity. The endonuclease active site appears to include a conserved motif, DQHA(X)2E(X)4E, within the COOH-terminus of human PMS2. Substitution of the glutamic acid residue (E705) abolished the endonuclease activity and mismatch-dependent excision in vitro. Previously, we showed that the PMS2-E705K mutation and the corresponding mutation in Saccharomyces cerevisiae were both recessive loss of function alleles for mutation avoidance in vivo. Here, we show that mutations impacting this endonuclease motif also significantly affect MMR-dependent suppression of homeologous recombination in yeast and responses to Sn1-type methylating agents in both yeast and mammalian cells. Thus, our in vivo results suggest that the endonuclease activity of MutLα is important not only in MMR-dependent mutation avoidance but also for recombination and damage response functions.

Original languageEnglish (US)
Pages (from-to)1463-1470
Number of pages8
JournalDNA Repair
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2007

Fingerprint

DNA Mismatch Repair
Endonucleases
Repair
Mutation
Yeast
Genetic Recombination
Yeasts
DNA
Machinery
Mutation Rate
Glutamic Acid
Substitution reactions
Cells
Saccharomyces cerevisiae
Catalytic Domain
Alleles

Keywords

  • Endonuclease
  • Methylation tolerance
  • Mismatch repair
  • MutLα
  • Recombination

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Mutations affecting a putative MutLα endonuclease motif impact multiple mismatch repair functions. / Erdeniz, Naz; Nguyen, Megan; Deschênes, Suzanne M.; Liskay, Robert (Mike).

In: DNA Repair, Vol. 6, No. 10, 01.10.2007, p. 1463-1470.

Research output: Contribution to journalArticle

Erdeniz, Naz ; Nguyen, Megan ; Deschênes, Suzanne M. ; Liskay, Robert (Mike). / Mutations affecting a putative MutLα endonuclease motif impact multiple mismatch repair functions. In: DNA Repair. 2007 ; Vol. 6, No. 10. pp. 1463-1470.
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