Transcriptional profiling of the age-related response to genotoxic stress points to differential DNA damage response with age.
The p53 DNA damage response attenuated with age and we have evaluated downstream factors in the DNA damage response. In old animals p21 protein accumulates in the whole cell fraction but significantly declines in the nucleus, which may alter cell cycle and apoptotic programs in response to DNA damage. We evaluated the transcriptional response to DNA damage in young and old and find 2692 genes are differentially regulated in old compared to young in response to oxidative stress (p<0.005). As anticipated, the transcriptional profile of young mice is consistent with DNA damage induced cell cycle arrest while the profile of old mice is consistent with cell cycle progression in the presence of DNA damage, suggesting the potential for catastrophic accumulation of DNA damage at the replication fork. Unique sets of DNA repair genes are induced in response to damage in old and young, suggesting the types of damage accumulating differs between young and old. The DNA repair genes upregulated in old animals point to accumulation of replication-dependent DNA double strand breaks (DSB). Expression data is consistent with loss of apoptosis following DNA damage in old animals. These data suggest DNA damage responses differ greatly in young and old animals.
Simon
Kirk
K
Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48084, United States.
Mukundan
Anju
A
Dewundara
Samantha
S
Van Remmen
Holly
H
Dombkowski
Alan A
AA
Cabelof
Diane C
DC
D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002273:Carcinogens / Q000494:pharmacology; D002453:Cell Cycle / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009595:Nitroparaffins / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D016133:Polymerase Chain Reaction; D011407:Propane / Q000031:analogs & derivatives / Q000494:pharmacology; D015203:Reproducibility of Results; D013047:Specific Pathogen-Free Organisms; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002273:Carcinogens; D009595:Nitroparaffins; D016159:Tumor Suppressor Protein p53; C016617:2-nitropropane; D011407:Propane
Mech Ageing Dev. 1997 Dec;98(3):203-22
9352490
Mech Ageing Dev. 2009 Mar;130(3):179-88
19071156
J Gerontol A Biol Sci Med Sci. 2006 May;61(5):427-34
16720738
Carcinogenesis. 2002 Sep;23(9):1419-25
12189182
Mech Ageing Dev. 1997 Dec;98(3):189-202
9352489
Proc Natl Acad Sci U S A. 2004 May 18;101(20):7624-9
15123826
Cell. 2005 Feb 25;120(4):513-22
15734683
J Mol Biol. 2007 Feb 9;366(1):36-52
17141802
Toxicol Sci. 2002 Oct;69(2):306-16
12377979
Mech Ageing Dev. 2003 Jul;124(7):847-50
12875748
Growth Dev Aging. 1993 Summer;57(2):85-100
8495997
Mech Ageing Dev. 1989 May;48(2):145-55
2661932
Nature. 2003 Nov 13;426(6963):194-8
14608368
Genes Dev. 1998 Jun 15;12(12):1871-83
9637688
Exp Gerontol. 1986;21(4-5):277-82
3545871
DNA Repair (Amst). 2007 May 1;6(5):639-48
17236818
Mol Cell Biol. 2005 Oct;25(19):8430-43
16166626
Nat Rev Cancer. 2004 Dec;4(12):948-55
15573116
Cancer Res. 2004 Jun 1;64(11):3748-52
15172978
EMBO J. 1998 Jan 15;17(2):598-608
9430650
Biogerontology. 2001;2(4):261-70
11868901
Nucleic Acids Res. 1998 Sep 1;26(17):3971-6
9705507
Nat Rev Mol Cell Biol. 2008 May;9(5):402-12
18431400
PLoS Biol. 2008 Dec 2;6(12):2853-68
19053174
EMBO J. 2001 Feb 15;20(4):914-23
11179235
Oncogene. 2002 Jan 24;21(5):731-7
11850801
Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):550-7
10673199
Mol Cell. 2002 Dec;10(6):1379-90
12504013
Cell. 2002 Jun 14;109(6):745-56
12086673
Mutat Res. 2006 Feb 22;594(1-2):189-98
16343558
Chem Biol Interact. 1994 Jun;92(1-3):67-76
8033271
J Gerontol A Biol Sci Med Sci. 2003 Mar;58(3):205-11
12634285
Mech Ageing Dev. 2006 Jan;127(1):16-24
16229875
Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1847-52
17264206
Mol Cell Biol. 2004 Aug;24(16):7140-50
15282313
Cancer Res. 2006 Aug 1;66(15):7460-5
16885342
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2410-5
14983023
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18143-7
17116885
Science. 2005 Jul 15;309(5733):481-4
16020738
Curr Biol. 1999 Jun 17;9(12):649-52
10375530
Mech Ageing Dev. 2002 Sep;123(11):1521-8
12425958
Mutat Res. 2002 Mar 20;500(1-2):135-45
11890943
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16633-8
17921246
J Biol Chem. 2008 May 23;283(21):14883-92
18337252
Mutat Res. 1995 Oct;338(1-6):25-34
7565878
Curr Biol. 2006 Oct 24;16(20):2009-15
17055979
Mol Cell Biol. 2005 Aug;25(16):7158-69
16055725
J Gerontol. 1989 Nov;44(6):45-54
2681362
J Biol Chem. 2004 May 14;279(20):21183-92
15016801
Proc Soc Exp Biol Med. 1991 Jul;197(3):297-303
1906180
Nat Cell Biol. 2004 Feb;6(2):168-70
14755273
FEBS Lett. 2002 Nov 6;531(2):319-23
12417334
J Biol Chem. 2005 Dec 23;280(51):42383-90
16236704
FASEB J. 2000 Jul;14(10):1325-34
10877825