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Polymerase delta and epsilon proofreading cooperate with MMR to suppress lethal mutations and cancer in mice
Author(s) -
Albertson Tina M.,
Hays Laura E.,
Bugni James M.,
Ogawa Masanori,
Treuting Piper M.,
Goldsby Robert E.,
Preston Bradley D.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.491.1
Subject(s) - proofreading , mlh1 , biology , dna polymerase , dna mismatch repair , genetics , mutation , cancer research , dna repair , dna , gene
Studies in yeast show that mismatch repair (MMR) and DNA polymerase (Pol) proofreading cooperate to ensure faithful DNA synthesis. However, the functional relationship of these pathways in mammals is not known. We recently reported that mice harboring defects in Pol δ proofreading ( Pold1 e ), Pol ε proofreading ( Pole e ) or MMR ( Mlh1 Δ ) have distinct mutator and cancer phenotypes (PNAS 106:17100, 2009). Intercrosses of Pol δ ‐, Pol ε‐, and MMR‐mutant mice showed that Pol δ and ε proofreading act in parallel pathways to prevent spontaneous mutation and cancer. In contrast, proofreading and MMR exhibited a synergistic relationship. The combined loss of proofreading and MMR was embryonic lethal; Pold1 e/e Mlh1 Δ/Δ embryos died early (E6–9) whereas Pole e/e Mlh1 Δ/Δ died late (E15–20) in development. Mice heterozygous for proofreading and nullizygous for MMR ( Pold1 +/e Mlh1 Δ/Δ or Pole +/e Mlh1 Δ/Δ ) were viable, but died of lymphoma and medulloblastoma before 3 months of age. Pole +/e Mlh1 Δ/Δ animals had accelerated cancer mortality compared to Pold1 +/e Mlh1 Δ/Δ mice and a higher neonatal mortality. Pold1 +/e Mlh1 Δ/Δ cells exhibited a “super‐mutator” phenotype, with spontaneous mutation rates 1000‐fold over wild‐type cells. These studies show that Pol δ and Pol ε proofreading act independently of one another and each cooperates with MMR to prevent lethal mutations and cancer in mice.