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DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice

Tina M. Albertson, Masanori Ogawa, James M. Bugni, Laura E. Hays, Yang Chen, Yanping Wang, Piper M. Treuting, John A. Heddle, Robert E. Goldsby, and Bradley D. Preston
PNAS October 6, 2009 106 (40) 17101-17104; https://doi.org/10.1073/pnas.0907147106
Tina M. Albertson
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Masanori Ogawa
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James M. Bugni
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Laura E. Hays
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Yang Chen
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Yanping Wang
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Piper M. Treuting
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John A. Heddle
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Robert E. Goldsby
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Bradley D. Preston
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  1. Edited by Allan H. Conney, Rutgers, The State University of New Jersey, Piscataway, NJ, and approved August 7, 2009 (received for review June 30, 2009)

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Abstract

Organisms require faithful DNA replication to avoid deleterious mutations. In yeast, replicative leading- and lagging-strand DNA polymerases (Pols ε and δ, 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 ε and δ proofreading suppress discrete mutator and cancer phenotypes. We found that inactivation of Pol ε 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 δ proofreading. Intercrosses of Pol ε-, Pol δ-, and mismatch repair-mutant mice show that Pol ε and δ proofreading act in parallel pathways to prevent spontaneous mutation and cancer. These findings distinguish Pol ε and δ functions in vivo and reveal tissue-specific requirements for DNA replication fidelity.

  • DNA replication
  • genetic instability
  • DNA polymerase fidelity
  • mismatch repair

Footnotes

  • 1To whom correspondence should be addressed. E-mail: bradp{at}u.washington.edu
  • Author contributions,: T.M.A., M.O., J.M.B., L.E.H., Y.C., Y.W., J.A.H., R.E.G., and B.D.P. designed research; T.M.A., M.O., J.M.B., L.E.H., Y.C., Y.W., and R.E.G. performed research; R.E.G. contributed new reagents/analytic tools; T.M.A., M.O., J.M.B., L.E.H., Y.C., Y.W., P.M.T., J.A.H., R.E.G., and B.D.P. analyzed data; and T.M.A. and B.D.P. wrote the paper.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/0907147106/DCSupplemental.

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DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice
Tina M. Albertson, Masanori Ogawa, James M. Bugni, Laura E. Hays, Yang Chen, Yanping Wang, Piper M. Treuting, John A. Heddle, Robert E. Goldsby, Bradley D. Preston
Proceedings of the National Academy of Sciences Oct 2009, 106 (40) 17101-17104; DOI: 10.1073/pnas.0907147106

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DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice
Tina M. Albertson, Masanori Ogawa, James M. Bugni, Laura E. Hays, Yang Chen, Yanping Wang, Piper M. Treuting, John A. Heddle, Robert E. Goldsby, Bradley D. Preston
Proceedings of the National Academy of Sciences Oct 2009, 106 (40) 17101-17104; DOI: 10.1073/pnas.0907147106
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