Defining the impact of mutation accumulation on replicative lifespan in yeast using cancer-associated mutator phenotypes.

Autor:	Lee MB; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Dowsett IT; Department of Pathology, University of Washington, Seattle, WA 98195-7705.; Molecular Medicine and Mechanisms of Disease Program, University of Washington, Seattle, WA 98195-7705., Carr DT; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Wasko BM; Department of Pathology, University of Washington, Seattle, WA 98195-7705.; Department of Biology and Biotechnology, University of Houston-Clear Lake, Houston, TX 77058., Stanton SG; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Chung MS; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Ghodsian N; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Bode A; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Kiflezghi MG; Department of Pathology, University of Washington, Seattle, WA 98195-7705.; Molecular Medicine and Mechanisms of Disease Program, University of Washington, Seattle, WA 98195-7705., Uppal PA; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Grayden KA; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Elala YC; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Tang TT; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Tran NHB; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Tran THB; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Diep AB; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Hope M; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Promislow DEL; Department of Pathology, University of Washington, Seattle, WA 98195-7705.; Department of Biology, University of Washington, Seattle, WA, 98195-1800., Kennedy SR; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Kaeberlein M; Department of Pathology, University of Washington, Seattle, WA 98195-7705., Herr AJ; Department of Pathology, University of Washington, Seattle, WA 98195-7705; alanherr@uw.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Feb 19; Vol. 116 (8), pp. 3062-3071. Date of Electronic Publication: 2019 Feb 04.
DOI:	10.1073/pnas.1815966116
Abstrakt:	Mutations accumulate within somatic cells and have been proposed to contribute to aging. It is unclear what level of mutation burden may be required to consistently reduce cellular lifespan. Human cancers driven by a mutator phenotype represent an intriguing model to test this hypothesis, since they carry the highest mutation burdens of any human cell. However, it remains technically challenging to measure the replicative lifespan of individual mammalian cells. Here, we modeled the consequences of cancer-related mutator phenotypes on lifespan using yeast defective for mismatch repair (MMR) and/or leading strand (Polε) or lagging strand (Polδ) DNA polymerase proofreading. Only haploid mutator cells with significant lifetime mutation accumulation (MA) exhibited shorter lifespans. Diploid strains, derived by mating haploids of various genotypes, carried variable numbers of fixed mutations and a range of mutator phenotypes. Some diploid strains with fewer than two mutations per megabase displayed a 25% decrease in lifespan, suggesting that moderate numbers of random heterozygous mutations can increase mortality rate. As mutation rates and burdens climbed, lifespan steadily eroded. Strong diploid mutator phenotypes produced a form of genetic anticipation with regard to aging, where the longer a lineage persisted, the shorter lived cells became. Using MA lines, we established a relationship between mutation burden and lifespan, as well as population doubling time. Our observations define a threshold of random mutation burden that consistently decreases cellular longevity in diploid yeast cells. Many human cancers carry comparable mutation burdens, suggesting that while cancers appear immortal, individual cancer cells may suffer diminished lifespan due to accrued mutation burden. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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