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

Published

April 9, 2013

Author(s)

Katarzyna Arczewska, Gisele Tomazella, Jessica Lindvall, Henok Kassahun, Silvia Maglioni, Alessandro Torgovnick, Johan Henriksson, Olli Matilainen, Bryce J. Marquis, Bryant Nelson, Eshrat Babaie, Carina Holmberg, Thomas Burglin, Natascia Ventura, Bernd Thiede, Hilde Nilsen

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

Pub Type

Journals

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Citation

Arczewska, K. , Tomazella, G. , Lindvall, J. , Kassahun, H. , Maglioni, S. , Torgovnick, A. , Henriksson, J. , Matilainen, O. , Marquis, B. , Nelson, B. , Babaie, E. , Holmberg, C. , Burglin, T. , Ventura, N. , Thiede, B. and Nilsen, H. (2013), Active Transcriptomic and Proteomic Reprogramming in the C. elegans Nucleotide Excision Repair Mutant xpa-1, Nucleic Acids Research, [online], https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=913265 (Accessed December 26, 2024)