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Published June 15, 2002 | public
Journal Article Open

Mutations in DNA Replication Genes Reduce Yeast Life Span


Surprisingly, the contribution of defects in DNA replication to the determination of yeast life span has never been directly investigated. We show that a replicative yeast helicase/nuclease, encoded by DNA2 and a member of the same helicase subfamily as the RecQ helicases, is required for normal life span. All of the phenotypes of old wild-type cells, for example, extended cell cycle time, age-related transcriptional silencing defects, and nucleolar reorganization, occur after fewer generations in dna2 mutants than in the wild type. In addition, the life span of dna2 mutants is extended by expression of an additional copy of SIR2 or by deletion of FOB1, which also increase wild-type life span. The ribosomal DNA locus and the nucleolus seem to be particularly sensitive to defects in dna2 mutants, although in dna2 mutants extrachromosomal ribosomal circles do not accumulate during the aging of a mother cell. Several other replication mutations, such as rad27{Delta}, encoding the FEN-1 nuclease involved in several aspects of genomic stability, also show premature aging. We propose that replication fork failure due to spontaneous, endogenous DNA damage and attendant genomic instability may contribute to replicative senescence. This may imply that the genomic instability, segmental premature aging symptoms, and cancer predisposition associated with the human RecQ helicase diseases, such as Werner, Bloom, and Rothmund-Thomson syndromes, are also related to replicative stress.

Additional Information

Copyright © 2002, American Society for Microbiology. Received 21 November 2001/Returned for modification 4 February 2002/Accepted 18 March 2002 We thank S. M. Jazwinski for invaluable help in setting up the life span determinations and G. M. Martin and Masayasu Nomura for reading an earlier form of the manuscript. We thank John Aris for the Nop1 antibody and the Caltech-ERATO center for use of the Nikon microscope for image processing, Jessica Brown for characterization of nucleoli in pol1-14, and Meghan McFarlane for dissection of some life spans. This research was supported by National Science Foundation POWRE grant MCB9805943 and by the Pomona College Research Committee (L.L.M.H). It was also supported by National Institutes of Health grant GM25508, National Science Foundation grant MCB9985527 to J.L.C., and National Science Foundation RUI grant MCB113937 to L.L.M.H.


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