dna replication stress is a determinant of chronological lifespan in budding yeastdna复制的压力是实足的行列式在出芽酵母寿命.pdfVIP

DNA Replication Stress Is a Determinant of Chronological Lifespan in Budding Yeast 1 1 2 3 3 3 4 4 Martin Weinberger , Li Feng , Anita Paul , Daniel L. Smith Jr. , Robert D. Hontz , Jeffrey S. Smith , Marija Vujcic , Keshav K. Singh , Joel A. 2 1 Huberman , William C. Burhans * 1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America, 2 Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America, 3 Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, Virginia, United States of America, 4 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, United States of America The chronological lifespan of eukaryotic organisms is extended by the mutational inactivation of conserved growth-signaling pathways that regulate progression into and through the cell cycle. Here we show that in the budding yeast S. cerevisiae, these and other lifespan-extending conditions, including caloric restriction and osmotic stress, increase the efficiency with which nutrient-depleted cells establish or maintain a cell cycle arrest in G1. Proteins required for efficient G1 arrest and longevity when nutrients are limiting include the DNA replication stress response proteins Mec1 and Rad53. Ectopic expression of CLN3 encoding a G1 cyclin downregulated during nutrient depletion increases the frequency with which nutrient depleted cells arrest growth in S phase instead of G1. Ectopic expression of CLN3 also shortens chronological lifespan in concert with age- dependent increases in genome instability and apoptosis. These findings indicate that replication stress is an