Regulators of global genome repair do not respond to DNA damaging therapy but correlate with survival in melanoma.
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.
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
Nikola A
NA
Bowden
Katie A
KA
Ashton
Ricardo E
RE
Vilain
Kelly A
KA
Avery-Kiejda
Ryan J
RJ
Davey
Heather C
HC
Murray
Timothy
T
Budden
Stephen G
SG
Braye
Xu Dong
XD
Zhang
Peter
P
Hersey
Rodney J
RJ
Scott
D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D064447:Checkpoint Kinase 2 / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D002945:Cisplatin