Active transcriptomic and proteomic reprogramming in the C. elegans nucleotide excision repair mutant xpa-1.
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Arczewska KD, Tomazella GG, Lindvall JM, Kassahun H, Maglioni S, Torgovnick A, Henriksson J, Matilainen O, Marquis BJ, Nelson BC, Jaruga P, Babaie E, Holmberg CI, Bürglin TR, Ventura N, Thiede B, Nilsen H
Nucleic Acids Res. 41 (10) 5368-5381 [2013-05-01; online 2013-04-13]
Transcription-blocking oxidative DNA damage is believed to contribute to aging and to underlie activation of oxidative stress responses and down-regulation of insulin-like signaling (ILS) in Nucleotide Excision Repair (NER) deficient mice. Here, we present the first quantitative proteomic description of the Caenorhabditis elegans NER-defective xpa-1 mutant and compare the proteome and transcriptome signatures. Both methods indicated activation of oxidative stress responses, which was substantiated biochemically by a bioenergetic shift involving increased steady-state reactive oxygen species (ROS) and Adenosine triphosphate (ATP) levels. We identify the lesion-detection enzymes of Base Excision Repair (NTH-1) and global genome NER (XPC-1 and DDB-1) as upstream requirements for transcriptomic reprogramming as RNA-interference mediated depletion of these enzymes prevented up-regulation of genes over-expressed in the xpa-1 mutant. The transcription factors SKN-1 and SLR-2, but not DAF-16, were identified as effectors of reprogramming. As shown in human XPA cells, the levels of transcription-blocking 8,5'-cyclo-2'-deoxyadenosine lesions were reduced in the xpa-1 mutant compared to the wild type. Hence, accumulation of cyclopurines is unlikely to be sufficient for reprogramming. Instead, our data support a model where the lesion-detection enzymes NTH-1, XPC-1 and DDB-1 play active roles to generate a genomic stress signal sufficiently strong to result in transcriptomic reprogramming in the xpa-1 mutant.
Bioinformatics and Expression Analysis (BEA)
PubMed 23580547
DOI 10.1093/nar/gkt225
Crossref 10.1093/nar/gkt225
pii: gkt225
pmc: PMC3664812