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Publication Citation: Active Transcriptomic and Proteomic Reprogramming in the C. elegans Nucleotide Excision Repair Mutant xpa-1

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Author(s): Katarzyna Arczewska; Gisele Tomazella; Jessica Lindvall; Henok Kassahun; Silvia Maglioni; Alessandro Torgovnick; Johan Henriksson; Olli Matilainen; Bryce J. Marquis; Bryant C. Nelson; Eshrat Babaie; Carina Holmberg; Thomas Burglin; Natascia Ventura; Bernd Thiede; Hilde Nilsen;
Title: Active Transcriptomic and Proteomic Reprogramming in the C. elegans Nucleotide Excision Repair Mutant xpa-1
Published: April 10, 2013
Abstract: 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 C. 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 ROS and 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 upregulation 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.
Citation: Nucleic Acids Research
Pages: pp. 1 - 14
Research Areas: Life Sciences Research, Bioscience & Health
PDF version: PDF Document Click here to retrieve PDF version of paper (2MB)