Abstract
The nucleotide excision repair pathway deals with UV-induced DNA damage. The tissue that receives by far the greatest exposure to UV is the skin and we have investigated the possibility that expression of the nucleotide excision repair gene, Ercc1, may display different properties in the skin to deal with a more demanding role in that tissue. ERCC1, in a complex with XPF, is the structure—specific endonuclease responsible for incising 5′ to the UV-induced lesion. We identified a novel Ercc1 mRNA in mouse skin that originates from an alternative upstream promoter. Levels of this skin-specific transcript were low in embryonic skin and increased rapidly after birth, but there was no induction by UV, either in adult skin, or in a cultured keratinocyte model. Levels of the skin-specific Ercc1 transcript were higher in albino than pigmented mouse strains, but there was no difference in ERCC1 protein levels and the expression of the skin-specific transcript was found to be determined by the Ercc1 gene sequence rather than by coat pigmentation. Using an Ercc1 transgene the promoter for the skin-specific transcript was mapped to a region around 400 bp upstream of the normal promoter, where a transposable element with known promoter activity was found in albino but not in pigmented strains.
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References
Adimoolam S, Ford JM (2002) p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene. Proc Natl Acad Sci USA 99:12985–12990
Chipchase MD, O’Neill M, Melton DW (2003) Characterisation of premature liver polyploidy in DNA repair (Ercc1)-deficient mice. Hepatology 38:958–966
de Boer J, Hoeijmakers JH (2000) Nucleotide excision repair and human syndromes. Carcinogenesis 21:453–460
Doig J, Anderson C, Lawrence NJ, Selfridge J, Brownstein DG, Melton DW (2006) Mice with skin-specific DNA repair gene (Ercc1) inactivation are hypersensitive to ultraviolet irradiation-induced skin cancer and show more rapid actinic progression. Oncogene 25:6229–6238
Ferrigno O, Virolle T, Djabari Z, Ortonne JP, White RJ, Aberdam D (2001) Transposable B2 SINE elements can provide mobile RNA polymerase II promoters. Nature Genet 28:77–81
Hsia KT, Millar MR, King S, Selfridge J, Redhead NJ, Melton DW, Saunders PTK (2003) DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse. Development 130:369–378
Hwang BJ, Ford JM, Hanawalt PC, Chu G (1999) Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc Natl Acad Sci USA 96:424–428
Kuraoka I, Kobertz WR, Ariza RR, Biggerstaff M, Essigmann JM, Wood RD (2000) Repair of interstrand DNA crosslink initiated by ERCC1-XPF repair/recombination nuclease. J Biol Chem 275:26632–26636
Lawrence NJ, Song L, Doig J, Ritchie A-M, Brownstein DG, Melton DW (2009) Topical thymidine dinucleotide application protects against UVB-induced skin cancer in mice with DNA repair gene (Ercc1)-deficient skin. DNA Repair 8:664–671
Magin TM, McWhir J, Melton DW (1992) A new mouse embryonic stem cell line with good germline contribution and gene targeting frequency. Nucleic Acids Res 20:3795–3796
Murakami T, Fujimoto M, Ohtsuki M, Nakagawa H (2001) Expression profiling of cancer-related genes in human keratinocytes following non-lethal ultraviolet B irradiation. J Dermatol Sci 27:121–129
Pennisi E (2007) Evolution: jumping genes hop into the evolutionary limelight. Science 317:894–895
Petit C, Sancar A (1999) Nucleotide excision repair: from E. coli to man. Biochimie 81:15–25
Pines A, Backendorf C, Alekseev S, Jansen JG, de Gruijl FR, Vrieling H, Mullenders LH (2009) Differential activity of UV-DDB in mouse keratinocytes and fibroblasts: impact on DNA repair and UV-induced skin cancer. DNA Repair 8:153–161
Prestridge DS (1995) Predicting Pol II promoter sequences using transcription factor binding sites. J Mol Biol 249:923–932
Sargent RG, Brenneman MA, Wilson JH (1997) Repair of site-specific double-strand breaks in a mammalian chromosome by homologous and illegitimate recombination. Mol Cell Biol 17:267–277
Selfridge J, Hsia KT, Redhead NJ, Melton DW (2001) Correction of liver dysfunction in DNA repair-deficient mice with an ERCC1 transgene. Nucleic Acids Res 29:4541–4550
Thierry-Mieg D, Thierry-Mieg J (2006) AceView: a comprehensive cDNA-supported gene and transcripts annotation. Genome Biol 7(Suppl 1):S12, 11–14
Thompson S, Clarke AR, Pow AM, Hooper ML, Melton DW (1989) Germ line transmission of a corrected HPRT gene produced by gene targeting in embryonic stem cells. Cell 56:313–321
Thornburg BG, Gotea V, Makalowski W (2006) Transposable elements as a significant source of transcription regulating signals. Gene 365:104–110
van Duin M, Koken MH, van den Tol J, ten Dijke P, Odijk H (1987) Genomic characterization of the human DNA excision repair gene ERCC-1. Nucleic Acids Res 15:9195–9213
van Duin MJ, van den Tol P, Warmerdam H, Odijk D, Meijer A, Westerveld D, Bootsma D, Hoeijmakers JH (1988) Evolution and mutagenesis of the mammalian excision repair gene ERCC-1. Nucleic Acids Res 16:5305–5322
Wilson MD, Ruttan CC, Koop BF, Glickman BW (2001) ERCC1: a comparative genomic perspective. Environ Mol Mutagen 38:209–215
Wood RD (1997) Nucleotide excision repair in mammalian cells. J Biol Chem 272:23465–23468
Acknowledgments
Ercc1 transgenes were constructed by Carolanne McEwan. The RT-PCR assay to discriminate between normal and skin-specific Ercc1 transcripts was developed by Nicola Redhead and was used on Ercc1 transgene transfectants by Yvonne Simpson. LS was supported by a PhD scholarship from the College of Medicine and Veterinary Medicine, University of Edinburgh. This work was supported by The University of Edinburgh.
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Song, L., Winter, A.G., Selfridge, J. et al. A novel transcript for DNA repair gene Ercc1 in mouse skin. Transgenic Res 20, 109–122 (2011). https://doi.org/10.1007/s11248-010-9396-3
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DOI: https://doi.org/10.1007/s11248-010-9396-3