Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system.
Werner and Bloom syndromes are human diseases characterized by premature age-related defects including elevated cancer incidence. Using a novel Saccharomyces cerevisiae model system for aging and cancer, we show that cells lacking the RecQ helicase SGS1 (WRN and BLM homologue) undergo premature age-related changes, including reduced life span under stress and calorie restriction (CR), G1 arrest defects, dedifferentiation, elevated recombination errors, and age-dependent increase in DNA mutations. Lack of SGS1 results in a 110-fold increase in gross chromosomal rearrangement frequency during aging of nondividing cells compared with that generated during the initial population expansion. This underscores the central role of aging in genomic instability. The deletion of SCH9 (homologous to AKT and S6K), but not CR, protects against the age-dependent defects in sgs1Delta by inhibiting error-prone recombination and preventing DNA damage and dedifferentiation. The conserved function of Akt/S6k homologues in lifespan regulation raises the possibility that modulation of the IGF-I-Akt-56K pathway can protect against premature aging syndromes in mammals.
Madia
Federica
F
Andrus Gerontology Center and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Gattazzo
Cristina
C
Wei
Min
M
Fabrizio
Paola
P
Burhans
William C
WC
Weinberger
Martin
M
Galbani
Abdoulaye
A
Smith
Jesse R
JR
Nguyen
Christopher
C
Huey
Selina
S
Comai
Lucio
L
Longo
Valter D
VD
D000367:Age Factors; D001816:Bloom Syndrome / Q000235:genetics*; D031204:Caloric Restriction; D002454:Cell Differentiation; D004249:DNA Damage; D016193:G1 Phase / Q000235:genetics; D017353:Gene Deletion; D042822:Genomic Instability; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics* / Q000502:physiology; D053484:RecQ Helicases / Q000235:genetics*; D011995:Recombination, Genetic / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D014898:Werner Syndrome / Q000235:genetics*
D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C071569:SCH9 protein kinase; C090472:SGS1 protein, S cerevisiae; D053484:RecQ Helicases