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

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

doi:10.1371/journal.pone.0070424

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

PLoS One. 2013 Aug 5;8(8):e70424. doi: 10.1371/journal.pone.0070424. Print 2013.

Authors

Nikola A Bowden¹, Katie A Ashton, Ricardo E Vilain, Kelly A Avery-Kiejda, Ryan J Davey, Heather C Murray, Timothy Budden, Stephen G Braye, Xu Dong Zhang, Peter Hersey, Rodney J Scott

Affiliation

¹ School of Biomedical Sciences & Pharmacy, Faculty of Health, University of Newcastle, Australia and Hunter Medical Research Institute, Newcastle, NSW, Australia. Nikola.Bowden@newcastle.edu.au

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ataxia Telangiectasia Mutated Proteins / genetics
BRCA1 Protein / genetics
BRCA2 Protein / genetics
Cell Line, Tumor
Cell Survival / drug effects
Checkpoint Kinase 2 / genetics
Cisplatin / pharmacology
DNA Damage / drug effects
DNA Damage / genetics
DNA Repair / drug effects
DNA Repair / genetics*
Humans
Melanoma / genetics
Melanoma / metabolism*

Substances

BRCA1 Protein
BRCA1 protein, human
BRCA2 Protein
BRCA2 protein, human
Checkpoint Kinase 2
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
CHEK2 protein, human
Cisplatin

Grants and funding

This work was supported by the Hunter Medical Research Institute; the University of Newcastle Centre for Information Based Medicine; the Cancer Council, New South Wales, Australia; Cancer Australia; and the Cure Cancer Australia Foundation. NB and RV are supported by the National Health & Medical Research Council. KA is supported by the Mrs. Joyce and Dr. George Bogner Estate and the Hunter Medical Research Institute. KAK is the recipient of the Cameron Melanoma Research Fellowship from the Melanoma and Skin Cancer Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.