Organisms require faithful DNA replication to avoid deleterious mutations. In yeast, replicative leading-and lagging-strand DNA polymerases (Pols and ␦, 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 and ␦ proofreading suppress discrete mutator and cancer phenotypes. We found that inactivation of Pol proofreading elevates basesubstitution mutations and accelerates a unique spectrum of spontaneous cancers; the types of tumors are entirely different from those triggered by loss of Pol ␦ proofreading. Intercrosses of Pol -, Pol ␦-, and mismatch repair-mutant mice show that Pol and ␦ proofreading act in parallel pathways to prevent spontaneous mutation and cancer. These findings distinguish Pol and ␦ functions in vivo and reveal tissue-specific requirements for DNA replication fidelity.DNA replication ͉ genetic instability ͉ DNA polymerase fidelity ͉ mismatch repair

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The workshop was designed to present what is known about the production of micronuclei, what protocols are now accepted or proposed internationally, what new results have been obtained, and what new methods and protocols are likely to be forthcoming. This report is designed to convey the flavour of the workshop and to provide the essence of the new information. After the workshop an effort was made to determine what single protocol would satisfy the requirements set for the micronucleus test by as many regulatory agencies as possible. The result, reported here, includes the requirements of six regulatory authorities in Canada, the European Economic Community, the Organization for Economic Co-operation and Development, Japan, and the United States.

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