title: DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice.
abstract: Organisms require faithful DNA replication to avoid deleterious mutations. In yeast, replicative leading- and lagging-strand DNA polymerases (Pols epsilon and delta, respectively) have intrinsic proofreading exonucleases that cooperate with each other and mismatch repair to limit spontaneous mutation to less than 1 per genome per cell division. The relationship of these pathways in mammals and their functions in vivo are unknown. Here we show that mouse Pol epsilon and delta proofreading suppress discrete mutator and cancer phenotypes. We found that inactivation of Pol epsilon proofreading elevates base-substitution mutations and accelerates a unique spectrum of spontaneous cancers; the types of tumors are entirely different from those triggered by loss of Pol delta proofreading. Intercrosses of Pol epsilon-, Pol delta-, and mismatch repair-mutant mice show that Pol epsilon and delta proofreading act in parallel pathways to prevent spontaneous mutation and cancer. These findings distinguish Pol epsilon and delta functions in vivo and reveal tissue-specific requirements for DNA replication fidelity.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195-7705, USA.
authors.forename: Tina M
authors.initials: TM
authors.lastname: Albertson
authors.forename: Masanori
authors.initials: M
authors.lastname: Ogawa
authors.forename: James M
authors.initials: JM
authors.lastname: Bugni
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hays
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Piper M
authors.initials: PM
authors.lastname: Treuting
authors.forename: John A
authors.initials: JA
authors.lastname: Heddle
authors.forename: Robert E
authors.initials: RE
authors.lastname: Goldsby
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Preston
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D004257:DNA Polymerase II / Q000235:genetics* / Q000378:metabolism; D004258:DNA Polymerase III / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D005838:Genotype; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D004257:DNA Polymerase II; D004258:DNA Polymerase III; C497173:Msh2 protein, mouse; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein