title: A two-tiered compensatory response to loss of DNA repair modulates aging and stress response pathways.
abstract: Activation of oxidative stress-responses and downregulation of insulin-like signaling (ILS) is seen in Nucleotide Excision Repair (NER) deficient segmental progeroid mice. Evidence suggests that this is a survival response to persistent transcription-blocking DNA damage, although the relevant lesions have not been identified. Here we show that loss of NTH-1, the only Base Excision Repair (BER) enzyme known to initiate repair of oxidative DNA damage inC. elegans, restores normal lifespan of the short-lived NER deficient xpa-1 mutant. Loss of NTH-1 leads to oxidative stress and global expression profile changes that involve upregulation of genes responding to endogenous stress and downregulation of ILS. A similar, but more extensive, transcriptomic shift is observed in the xpa-1 mutant whereas loss of both NTH-1 and XPA-1 elicits a different profile with downregulation of Aurora-B and Polo-like kinase 1 signaling networks as well as DNA repair and DNA damage response genes. The restoration of normal lifespan and absence oxidative stress responses in nth-1;xpa-1 indicate that BER contributes to generate transcription blocking lesions from oxidative DNA damage. Hence, our data strongly suggests that the DNA lesions relevant for aging are repair intermediates resulting from aberrant or attempted processing by BER of lesions normally repaired by NER.
authors.affiliation: University of Oslo, The Biotechnology Centre, Blindern, Oslo, Norway.
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Fensgård
authors.forename: Henok
authors.initials: H
authors.lastname: Kassahun
authors.forename: Izabela
authors.initials: I
authors.lastname: Bombik
authors.forename: Torbjørn
authors.initials: T
authors.lastname: Rognes
authors.forename: Jessica Margareta
authors.initials: JM
authors.lastname: Lindvall
authors.forename: Hilde
authors.initials: H
authors.lastname: Nilsen
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045647:DNA Glycosylases; D004260:DNA Repair; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D064107:Aurora Kinase B; D064127:Aurora Kinases; D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D045647:DNA Glycosylases; D004720:Endonucleases; D007328:Insulin; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051760:Xeroderma Pigmentosum Group A Protein; D000097869:Polo-Like Kinase 1; C553374:XPA-1 protein, C elegans; C576924:Aurkb protein, mouse; C553373:NTH-1 protein, C elegans
references.citation: DNA Repair (Amst). 2008 Feb 1;7(2):267-80
references.pmid: 18053776
references.citation: Cell Metab. 2009 Nov;10(5):379-91
references.pmid: 19883616
references.citation: BMC Genomics. 2008 Jul 15;9:334
references.pmid: 18627611
references.citation: Cell. 1995 Mar 24;80(6):859-68
references.pmid: 7697716
references.citation: Genome Res. 2003 Nov;13(11):2498-504
references.pmid: 14597658
references.citation: Bioinformatics. 2005 Aug 15;21(16):3448-9
references.pmid: 15972284
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9463-8
references.pmid: 9256505
references.citation: Dev Cell. 2002 Jan;2(1):41-54
references.pmid: 11782313
references.citation: PLoS One. 2007 Nov 28;2(11):e1252
references.pmid: 18043759
references.citation: Nature. 2003 Jul 17;424(6946):277-83
references.pmid: 12845331
references.citation: J Cell Physiol. 2008 Mar;214(3):721-9
references.pmid: 17894411
references.citation: Genome Res. 2009 Jun;19(6):1107-16
references.pmid: 19246318
references.citation: FEBS Lett. 2000 Jun 30;476(1-2):73-7
references.pmid: 10878254
references.citation: J Gerontol. 1956 Jul;11(3):298-300
references.pmid: 13332224
references.citation: Genetics. 2006 Sep;174(1):57-65
references.pmid: 16783005
references.citation: PLoS Biol. 2007 Jan;5(1):e2
references.pmid: 17326724
references.citation: Cell Death Differ. 2006 Dec;13(12):2129-39
references.pmid: 16729024
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):3832-7
references.pmid: 10759556
references.citation: Mutagenesis. 2008 Sep;23(5):407-13
references.pmid: 18524757
references.citation: J Cell Biol. 2006 Jun 5;173(5):673-83
references.pmid: 16754955
references.citation: Ann N Y Acad Sci. 2002 Apr;959:466-74
references.pmid: 11976220
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12992-6
references.pmid: 15326288
references.citation: Mol Cell Biol. 1999 Apr;19(4):2929-35
references.pmid: 10082560
references.citation: Nucleic Acids Res. 2004 Jul 14;32(12):3712-23
references.pmid: 15254273
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Free Radic Biol Med. 2008 Oct 15;45(8):1167-77
references.pmid: 18708137
references.citation: Curr Biol. 2008 Sep 23;18(18):1355-64
references.pmid: 18804378
references.citation: Nat Cell Biol. 2009 May;11(5):604-15
references.pmid: 19363488
references.citation: J Inherit Metab Dis. 2002 May;25(3):197-206
references.pmid: 12137228
references.citation: Cell. 2005 Feb 25;120(4):449-60
references.pmid: 15734678
references.citation: EMBO J. 2008 Mar 19;27(6):876-85
references.pmid: 18309293
references.citation: PLoS Genet. 2007 Sep;3(9):1565-71
references.pmid: 17907808
references.citation: Genes Dev. 2003 Feb 15;17(4):443-8
references.pmid: 12600937
references.citation: Genome Biol. 2003;4(5):P3
references.pmid: 12734009
references.citation: Nature. 1993 Dec 2;366(6454):461-4
references.pmid: 8247153
references.citation: Mech Ageing Dev. 2009 Jun;130(6):357-69
references.pmid: 19428455
references.citation: Ann N Y Acad Sci. 2006 May;1067:120-8
references.pmid: 16803977
references.citation: Nucleic Acids Res. 2008 Mar;36(4):1380-9
references.pmid: 18203746
references.citation: Genetics. 1974 May;77(1):71-94
references.pmid: 4366476
references.citation: Cell. 2005 Feb 25;120(4):437-47
references.pmid: 15734677
references.citation: J Biol Chem. 2004 May 21;279(21):22585-94
references.pmid: 15020594
references.citation: Annu Rev Genet. 2004;38:445-76
references.pmid: 15568983
references.citation: DNA Repair (Amst). 2009 Jul 4;8(7):844-51
references.pmid: 19481506
references.citation: Crit Rev Oncog. 2008;14(4):217-73
references.pmid: 19645683
references.citation: Nat Cell Biol. 2008 Nov;10(11):1241-7
references.pmid: 18978832
references.citation: Mech Ageing Dev. 2005 Jun-Jul;126(6-7):642-7
references.pmid: 15888317
references.citation: Genome Biol. 2007;8(5):R70
references.pmid: 17472752
references.citation: Aging Cell. 2003 Apr;2(2):111-21
references.pmid: 12882324
references.citation: Curr Opin Cell Biol. 2008 Dec;20(6):650-60
references.pmid: 19000759
references.citation: Free Radic Biol Med. 2002 Jun 15;32(12):1244-53
references.pmid: 12057762
references.citation: Biochem J. 2008 Jan 1;409(1):205-13
references.pmid: 17714076
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19046-50
references.pmid: 18025456
references.citation: Biochem J. 2002 Jul 15;365(Pt 2):547-53
references.pmid: 11966472
references.citation: Genetics. 1982 Oct;102(2):159-78
references.pmid: 7152245
references.citation: Genetics. 1989 Jun;122(2):379-85
references.pmid: 2767423
references.citation: Nature. 1993 Apr 22;362(6422):709-15
references.pmid: 8469282