The Mammalian Mismatch Repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool

Claudia Colussi, Eleonora Parlanti, Paolo Degan, Gabriele Aquilina, Deborah Barnes, Peter Macpherson, Peter Karran, Marco Crescenzi, Eugenia Dogliotti, Margherita Bignami

Research output: Contribution to journalArticlepeer-review

Abstract

Mismatch repair (MIMR) corrects replication errors. It requires the MSH2, MSH6, MLH1, and PMS2 proteins which comprise the MlutSα and MutLα heterodimers [1]. Inactivation of MSH2 or MLH1 in human tumors greatly increases spontaneous mutation rates [2]. Oxidation produces many detrimental DNA alterations against which cells deploy multiple protective strategies [3]. The Ogg-1 DNA glycosylase initiates base excision repair (BER) of 8-oxoguanine (8-oxoG) from 8-oxoG:C pairs [4]. The Myh DNA glycosylase removes mismatched adenines incorporated opposite 8-oxoG during replication [5]. Subsequent BER generates 8-oxoG:C pairs, a substrate for excision by Ogg-1. MTH1--an 8-oxodGTPase which eliminates 8-oxodGTP from the dNTP pool--affords additional protection by minimizing 8-oxodGMP incorporation during replication [6]. Here we show that the dNTP pool is, nevertheless, an important source of DNA 8-oxoG and that MMR provides supplementary protection by excising incorporated 8-oxodGMP. Incorporated 8-oxodGMP contributes significantly to the mutator phenotype of MMR-deficient cells. Thus, although BER of 8-oxoG is independent of Msh2, both steady-state and H2O2-induced DNA 8-oxoG levels are higher in Msh2-defective cells than in their repair-proficient counterparts. Increased expression of MTH1 in MMR-defective cells significantly reduces steady-state and H2O2-induced DNA 8-oxoG levels. This reduction dramatically diminishes the spontaneous mutation rate of Msh2-/- MEFs.

Original languageEnglish
Pages (from-to)912-918
Number of pages7
JournalCurrent Biology
Volume12
Issue number11
DOIs
Publication statusPublished - Jun 4 2002

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

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