Similar Nucleotide Excision Repair Capacity in Melanocytes and Melanoma Cells

Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Cancer Research (Impact Factor: 9.28). 06/2010; 70(12):4922-30. DOI: 10.1158/0008-5472.CAN-10-0095
Source: PubMed

ABSTRACT Sunlight UV exposure produces DNA photoproducts in skin that are repaired solely by nucleotide excision repair in humans. A significant fraction of melanomas are thought to result from UV-induced DNA damage that escapes repair; however, little evidence is available about the functional capacity of normal human melanocytes, malignant melanoma cells, and metastatic melanoma cells to repair UV-induced photoproducts in DNA. In this study, we measured nucleotide excision repair in both normal melanocytes and a panel of melanoma cell lines. Our results show that in 11 of 12 melanoma cell lines tested, UV photoproduct repair occurred as efficiently as in primary melanocytes. Importantly, repair capacity was not affected by mutation in the N-RAS or B-RAF oncogenes, nor was a difference observed between a highly metastatic melanoma cell line (A375SM) or its parental line (A375P). Lastly, we found that although p53 status contributed to photoproduct removal efficiency, its role did not seem to be mediated by enhanced expression or activity of DNA binding protein DDB2. We concluded that melanoma cells retain capacity for nucleotide excision repair, the loss of which probably does not commonly contribute to melanoma progression.

Download full-text


Available from: Michael G Kemp, Dec 16, 2013
  • Source
    • "Although somatic mutations have not previously been reported in NER genes in melanoma (www., and some nonacral melanoma cell lines retain NER activity (Bowden et al. 2010; Gaddameedhi et al. 2010), ERCC5 mutations are associated with microsatellite instability in colorectal and gastric cancers (Park et al. 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Next generation sequencing has enabled systematic discovery of mutational spectra in cancer samples. Here, we used whole genome sequencing to characterize somatic mutations and structural variation in a primary acral melanoma and its lymph node metastasis. Our data show that the somatic mutational rates in this acral melanoma sample pair were more comparable to the rates reported in cancer genomes not associated with mutagenic exposure than in the genome of a melanoma cell line or the transcriptome of melanoma short-term cultures. Despite the perception that acral skin is sun-protected, the dominant mutational signature in these samples is compatible with damage due to ultraviolet light exposure. A nonsense mutation in ERCC5 discovered in both the primary and metastatic tumors could also have contributed to the mutational signature through accumulation of unrepaired dipyrimidine lesions. However, evidence of transcription-coupled repair was suggested by the lower mutational rate in the transcribed regions and expressed genes. The primary and the metastasis are highly similar at the level of global gene copy number alterations, loss of heterozygosity and single nucleotide variation (SNV). Furthermore, the majority of the SNVs in the primary tumor were propagated in the metastasis and one nonsynonymous coding SNV and one splice site mutation appeared to arise de novo in the metastatic lesion.
    Genome Research 12/2011; 22(2):196-207. DOI:10.1101/gr.125591.111 · 13.85 Impact Factor
  • Source
    • "This process involves the formation of mutations at sites of DNA damage and, ultimately, results in malignant transformation after the accumulation of a sufficient number of mutations in critical genes (Runger, 2007). These mutations can occur in tumor suppressor genes such as p53 (Brash et al., 1991; Hussein et al., 2003; Rees, 1994; Ziegler et al., 1994; Ziegler et al., 1993), CDKN2/p16 (Holly et al., 1995; Saridaki et al., 2003; Soufir et al., 1999; Sparrow et al., 1998), and PTCH (D'Errico et al., 2000; Daya-Grosjean & Sarasin, 2000; de Gruijl et al., 2001; Ping et al., 2001; Zhang et al., 2001) as well as proto-oncogenes such as RAS (Chan et al., 2002; Kreimer-Erlacher et al., 2001; Spencer et al., 1995; van der Schroeff et al., 1990) and RAF (Besaratinia & Pfeifer, 2008; Gaddameedhi et al., 2010). UV-induced DNA damage also induces transcriptional activation of proto-oncogene c-fos (Ghosh et al., 1993). "
    Skin Cancers - Risk Factors, Prevention and Therapy, 11/2011; , ISBN: 978-953-307-722-2
  • Source
    Pigment Cell & Melanoma Research 10/2010; 24(1):119-24. DOI:10.1111/j.1755-148X.2010.00789.x · 5.64 Impact Factor
Show more