title: Active transcriptomic and proteomic reprogramming in the C. elegans nucleotide excision repair mutant xpa-1.
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 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.
authors.affiliation: The Biotechnology Centre, University of Oslo, PO Box 1125 Blindern, 0317 Oslo, Norway.
authors.forename: Katarzyna D
authors.initials: KD
authors.lastname: Arczewska
authors.forename: Gisele G
authors.initials: GG
authors.lastname: Tomazella
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Lindvall
authors.forename: Henok
authors.initials: H
authors.lastname: Kassahun
authors.forename: Silvia
authors.initials: S
authors.lastname: Maglioni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Torgovnick
authors.forename: Johan
authors.initials: J
authors.lastname: Henriksson
authors.forename: Olli
authors.initials: O
authors.lastname: Matilainen
authors.forename: Bryce J
authors.initials: BJ
authors.lastname: Marquis
authors.forename: Bryant C
authors.initials: BC
authors.lastname: Nelson
authors.forename: Pawel
authors.initials: P
authors.lastname: Jaruga
authors.forename: Eshrat
authors.initials: E
authors.lastname: Babaie
authors.forename: Carina I
authors.initials: CI
authors.lastname: Holmberg
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Bürglin
authors.forename: Natascia
authors.initials: N
authors.lastname: Ventura
authors.forename: Bernd
authors.initials: B
authors.lastname: Thiede
authors.forename: Hilde
authors.initials: H
authors.lastname: Nilsen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics; D004260:DNA Repair; D004720:Endonucleases / Q000235:genetics; D009154:Mutation; D020543:Proteome; D011687:Purines / Q000378:metabolism; D059467:Transcriptome; D057149:Ubiquitinated Proteins / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
chemical_list: D000975:Antioxidants; D029742:Caenorhabditis elegans Proteins; D020543:Proteome; D011687:Purines; D057149:Ubiquitinated Proteins; C553374:XPA-1 protein, C elegans; D051760:Xeroderma Pigmentosum Group A Protein; D004720:Endonucleases; D045647:DNA Glycosylases; C553373:NTH-1 protein, C elegans