title: The mammalian mismatch repair pathway removes DNA 8-oxodGMP incorporated from the oxidized dNTP pool.
abstract: Mismatch repair (MMR) corrects replication errors. It requires the MSH2, MSH6, MLH1, and PMS2 proteins which comprise the MutSalpha and MutLalpha heterodimers. Inactivation of MSH2 or MLH1 in human tumors greatly increases spontaneous mutation rates. Oxidation produces many detrimental DNA alterations against which cells deploy multiple protective strategies. The Ogg-1 DNA glycosylase initiates base excision repair (BER) of 8-oxoguanine (8-oxoG) from 8-oxoG:C pairs. The Myh DNA glycosylase removes mismatched adenines incorporated opposite 8-oxoG during replication. 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. 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 H(2)O(2)-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 H(2)O(2)-induced DNA 8-oxoG levels. This reduction dramatically diminishes the spontaneous mutation rate of Msh2(-/-) MEFs.
authors.affiliation: Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanita', Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Colussi
authors.forename: Eleonora
authors.initials: E
authors.lastname: Parlanti
authors.forename: Paolo
authors.initials: P
authors.lastname: Degan
authors.forename: Gabriele
authors.initials: G
authors.lastname: Aquilina
authors.forename: Deborah
authors.initials: D
authors.lastname: Barnes
authors.forename: Peter
authors.initials: P
authors.lastname: Macpherson
authors.forename: Peter
authors.initials: P
authors.lastname: Karran
authors.forename: Marco
authors.initials: M
authors.lastname: Crescenzi
authors.forename: Eugenia
authors.initials: E
authors.lastname: Dogliotti
authors.forename: Margherita
authors.initials: M
authors.lastname: Bignami
mesh_terms: D000818:Animals; D020137:Base Pair Mismatch; D004260:DNA Repair; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D006157:Guanosine Monophosphate / Q000378:metabolism*; D008322:Mammals; D010084:Oxidation-Reduction
chemical_list: D003848:Deoxyguanine Nucleotides; C078206:8-oxodeoxyguanosine triphosphate; D006157:Guanosine Monophosphate