A two-tiered compensatory response to loss of DNA repair modulates aging and stress response pathways.
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.
Fensgård
Øyvind
Ø
University of Oslo, The Biotechnology Centre, Blindern, Oslo, Norway.
Kassahun
Henok
H
Bombik
Izabela
I
Rognes
Torbjørn
T
Lindvall
Jessica Margareta
JM
Nilsen
Hilde
H
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
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
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