Regulators of global genome repair do not respond to DNA damaging therapy but correlate with survival in melanoma.

Nikola A Bowden,Peter Hersey,Kelly A Avery-Kiejda,Ricardo E Vilain,Katie A Ashton,Rodney J Scott,Timothy Budden,Stephen G Braye,Xu Dong Zhang,Heather C Murray,Ryan J Davey,John D Minna

doi:10.1371/journal.pone.0070424

Abstract

Nucleotide excision repair (NER) orchestrates the repair of helix distorting DNA damage, induced by both ultraviolet radiation (UVR) and cisplatin. There is evidence that the global genome repair (GGR) arm of NER is dysfunctional in melanoma and it is known to have limited induction in melanoma cell lines after cisplatin treatment. The aims of this study were to examine mRNA transcript levels of regulators of GGR and to investigate the downstream effect on global transcript expression in melanoma cell lines after cisplatin treatment and in melanoma tumours. The GGR regulators, BRCA1 and PCNA, were induced in melanocytes after cisplatin, but not in melanoma cell lines. Transcripts associated with BRCA1, BRCA2, ATM and CHEK2 showed altered expression in melanoma cell lines after cisplatin treatment. In melanoma tumour tissue BRCA1 transcript expression correlated with poor survival and XPB expression correlated with solar elastosis levels. Taken together, these findings provide evidence of the mechanisms underlying NER deficiency in melanoma.

Highlights

Nucleotide excision repair (NER) is primarily associated with the repair of the ultraviolet light radiation (UVR) induced lesions, cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP) [1]
We have previously reported the transcript expression levels of p53 were not significantly different in the melanoma cell lines compared to the melanocyte cell line 24 hours after cisplatin treatment as assessed by real-time PCR analysis [9]
Using a Natural Language Processing (NLP) algorithm and whole transcriptome gene expression data, we identified p53, BRCA1 and PCNA as transcriptional regulators of global genome repair (GGR). p53 was induced in melanocytes after cisplatin treatment in our previous study [9] and BRCA1 and PCNA were significantly induced in melanocytes after cisplatin in this study. p53, BRCA1 and PCNA were not induced in the Transcripts altered in melanocytes 24 hours after cisplatin treatment

Summary

Introduction

Nucleotide excision repair (NER) is primarily associated with the repair of the ultraviolet light radiation (UVR) induced lesions, cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP) [1]. Cisplatin is a common DNA-damaging agent that is used in the treatment of many types of malignancy [2]. Cisplatin binds to DNA forming similar helix distorting intra- and inter-strand cross-links [3,4] which must be removed prior to either transcription or DNA replication. Accumulation of cisplatin-induced DNA damage results in cellular death. The removal and repair of large helix distorting DNA damage induced by cisplatin is orchestrated by NER [5]. The versatility of NER suggests that this mechanism may play a pivotal role in resistance to treatment and development of cancer

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