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Restoring DNA repair capacity of cells from three distinct diseases by XPD gene-recombinant adenovirus

Cancer Gene Therapy volume 12, pages 389–396 (2005)Cite this article

Abstract

The nucleotide excision repair (NER) is one of the major human DNA repair pathways. Defects in one of the proteins that act in this system result in three distinct autosomal recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). TFIIH is a nine-protein complex essential for NER activity, initiation of RNA polymerase II transcription and with a possible role in cell cycle regulation. XPD is part of the TFIIH complex and has a helicase function, unwinding the DNA in the 5′ → 3′ direction. Mutations in the XPD gene are found in XP, TTD and XP/CS patients, the latter exhibiting both XP and CS symptoms. Correction of DNA repair defects of these cells by transducing the complementing wild-type gene is one potential strategy for helping these patients. Over the last years, adenovirus vectors have been largely used in gene delivering because of their efficient transduction, high titer, and stability. In this work, we present the construction of a recombinant adenovirus carrying the XPD gene, which is coexpressed with the EGFP reporter gene by an IRES sequence, making it easier to follow cell infection. Infection by this recombinant adenovirus grants full correction of SV40-transformed and primary skin fibroblasts obtained from XP-D, TTD and XP/CS patients.

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Acknowledgements

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP (São Paulo, Brazil), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brasília, Brazil) and CAPES-COFECUB (Brasilia; Brazil/Aix en Provence, France). MGA and KMLB have PhD fellowships from FAPESP. We thank Drs CFP Lofti (University of Sao Paulo, SP, Brazil), A Lehmann (MRC, Brighton, UK) and EC Friedberg (University of Texas Southwestern Medical Center at Dallas, TX) for providing some of the cell lines used in this work.

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Authors and Affiliations

  1. Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, 05508-900 SP, Brazil

    Melissa Gava Armelini, Maria Carolina Nasser Marchetto, Keronninn Moreno de Lima-Bessa & Carlos Frederico Martins Menck

  2. Laboratory of Genetics, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California, 92037, USA

    Alysson Renato Muotri

  3. Laboratory of Genetic Instability and Cancer, UPR 2169, Institut Gustave Roussy (IGR), 94805, Villejuif, France

    Alain Sarasin

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  1. Melissa Gava Armelini
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Correspondence to Carlos Frederico Martins Menck.

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Armelini, M., Muotri, A., Marchetto, M. et al. Restoring DNA repair capacity of cells from three distinct diseases by XPD gene-recombinant adenovirus. Cancer Gene Ther 12, 389–396 (2005). https://doi.org/10.1038/sj.cgt.7700797

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