DNA replication stress is a determinant of chronological lifespan in budding yeast.
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 important determinant of chronological lifespan in budding yeast. Protection from replication stress by growth-inhibitory effects of caloric restriction, osmotic and other stresses may contribute to hormesis effects on lifespan. Replication stress also likely impacts the longevity of higher eukaryotes, including humans.
Weinberger
Martin
M
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Feng
Li
L
Paul
Anita
A
Smith
Daniel L
DL
Hontz
Robert D
RD
Smith
Jeffrey S
JS
Vujcic
Marija
M
Singh
Keshav K
KK
Huberman
Joel A
JA
Burhans
William C
WC
D000375:Aging / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D031204:Caloric Restriction; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D016193:G1 Phase / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D008136:Longevity / Q000235:genetics*; D009997:Osmotic Pressure; D016196:S Phase / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological
C079895:CLN3 protein, S cerevisiae; D016213:Cyclins; D029701:Saccharomyces cerevisiae Proteins
Mol Cell. 2003 Dec;12(6):1607-13
14690612
Genes Dev. 1998 Sep 15;12(18):2943-55
9744870
Proc Natl Acad Sci U S A. 1989 Aug;86(15):5918-22
2762304
Science. 2001 Apr 13;292(5515):288-90
11292860
Genes Dev. 2005 Dec 15;19(24):3055-69
16357221
Mol Cell. 2002 May;9(5):1067-78
12049742
Mol Microbiol. 2001 Mar;39(5):1166-73
11251834
Genes Dev. 2006 Jan 15;20(2):174-84
16418483
Nature. 2005 Apr 14;434(7035):907-13
15829965
Science. 2005 Nov 18;310(5751):1193-6
16293764
J Gerontol. 1956 Jul;11(3):298-300
13332224
J Cell Biol. 2004 Feb 16;164(4):501-7
14970189
Annu Rev Genet. 2002;36:617-56
12429704
Cell. 2003 Nov 26;115(5):537-49
14651846
BMC Evol Biol. 2006 Jul 21;6:58
16859541
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1768-73
16446459
Microbiol Mol Biol Rev. 1998 Dec;62(4):1191-243
9841670
Cell Metab. 2007 Apr;5(4):265-77
17403371
Mol Cell. 2005 Apr 15;18(2):171-83
15837421
EMBO J. 1988 Dec 20;7(13):4335-46
2907481
Annu Rev Neurosci. 2001;24:1121-59
11520930
Science. 2003 Feb 28;299(5611):1342-6
12610293
EMBO J. 1998 Aug 3;17(15):4370-8
9687505
Microbiol Mol Biol Rev. 2006 Mar;70(1):253-82
16524925
Genes Dev. 2002 Oct 15;16(20):2639-49
12381663
Curr Biol. 2006 Feb 7;16(3):230-41
16461276
Mech Ageing Dev. 2005 Sep;126(9):987-1002
15893363
Genetics. 2003 Jan;163(1):35-46
12586694
FEBS Lett. 2004 Jan 16;557(1-3):136-42
14741356
Mol Cell Biol. 2002 Jun;22(12):4136-46
12024027
Mol Cell Biol. 1997 Nov;17(11):6491-501
9343412
Cell. 1984 Jun;37(2):437-45
6327067
Cell. 2005 Feb 25;120(4):497-512
15734682
Science. 2000 Sep 22;289(5487):2126-8
11000115
Nature. 2005 Apr 14;434(7035):864-70
15829956
Genes Dev. 1998 Sep 15;12(18):2956-70
9744871
Microbiol Mol Biol Rev. 2003 Sep;67(3):376-99, table of contents
12966141
J Biol Chem. 2006 Nov 17;281(46):34759-67
16968694
EMBO J. 1998 Jul 1;17(13):3556-64
9649426
J Cell Sci. 2005 Aug 1;118(Pt 15):3543-53
16079294
Mol Microbiol. 2001 Feb;39(4):1022-35
11251821
Methods Enzymol. 1991;194:3-21
2005794
Cell Cycle. 2004 Apr;3(4):462-8
15300954
Mol Microbiol. 1996 Mar;19(6):1159-66
8730858
J Bacteriol. 1980 Sep;143(3):1384-94
6997270
J Biol Chem. 1998 Apr 10;273(15):8564-71
9535829
Nat Rev Genet. 2005 Nov;6(11):866-72
16304601
Mol Gen Genet. 1980;178(2):357-60
6993845
Aging Cell. 2007 Oct;6(5):649-62
17711561
Endocrinology. 2005 Sep;146(9):3713-7
15919745
Nature. 1998 Oct 8;395(6702):615-8
9783589
EMBO J. 2005 Dec 21;24(24):4271-8
16308562
Cell Div. 2006 Apr 03;1:3
16759348
Mol Cell. 1998 Sep;2(3):329-40
9774971
Physiol Genomics. 2003 Dec 16;16(1):29-37
14679299
Mol Biol Cell. 1996 Jan;7(1):25-42
8741837
Nat Cell Biol. 2004 Oct;6(10):997-1002
15448699
Mol Microbiol. 2007 Mar;63(5):1482-94
17302822
J Cell Biol. 2006 Jul 3;174(1):89-100
16818721
Genetics. 2006 Sep;174(1):87-99
16816422
FEMS Yeast Res. 2003 Oct;4(1):7-13
14554192
Mol Biol Cell. 2000 Dec;11(12):4241-57
11102521
Methods Enzymol. 1991;194:1-863
2005781
Trends Cell Biol. 2003 Sep;13(9):493-501
12946629
Annu Rev Med. 2003;54:131-52
12525670
Cancer Res. 2006 Nov 1;66(21):10505-12
17079472
Cell. 2005 Mar 11;120(5):587-98
15766523
Mol Cell Biol. 2000 Dec;20(23):9076-83
11074005
J Cell Biol. 2004 Sep 27;166(7):1055-67
15452146
Cell. 2005 Feb 25;120(4):483-95
15734681
Mol Cell Biol. 1988 Nov;8(11):4675-84
3062366
J Bacteriol. 1998 Sep;180(17):4508-15
9721289
Science. 2003 Feb 28;299(5611):1355-9
12610296
Genes Dev. 2006 Jan 15;20(2):159-73
16384935
Mol Biol Cell. 2001 Jan;12(1):53-62
11160822
Genes Dev. 1997 Nov 15;11(22):3032-45
9367985
Nature. 1998 Oct 8;395(6702):618-21
9783590
Genetics. 2004 Jul;167(3):1109-21
15280227
PLoS Med. 2007 Mar;4(3):e76
17341128
Mol Cell Biol. 2005 Dec;25(23):10273-85
16287844
PLoS Biol. 2004 May;2(5):E128
15138498
Cell. 2005 Nov 18;123(4):655-67
16286010
Mol Microbiol. 2005 Feb;55(3):862-80
15661010
Science. 2005 Oct 14;310(5746):314-7
16224023
Mol Cell Biol. 2002 Nov;22(22):8056-66
12391171
Ann N Y Acad Sci. 2004 Jun;1019:388-91
15247051
Science. 1997 Oct 24;278(5338):680-6
9381177