School of Biomedical Sciences & Pharmacy, Faculty of Health, University of Newcastle, Australia and Hunter Medical Research Institute, Newcastle, NSW, Australia.
PLoS One. 2013 Aug 5;8(8):e70424. doi: 10.1371/journal.pone.0070424. Print 2013.
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.
核苷酸切除修复 (NER) 协调修复由紫外线 (UVR) 和顺铂诱导的扭曲 DNA 损伤的螺旋。有证据表明，NER 的全基因组修复 (GGR) 臂在黑色素瘤中功能失调，并且已知在顺铂处理后黑色素瘤细胞系中的诱导有限。本研究的目的是检查 GGR 调节剂的 mRNA 转录本水平，并研究顺铂处理后黑色素瘤细胞系和黑色素瘤肿瘤中全局转录表达的下游效应。BRCA1 和 PCNA 等 GGR 调节剂在顺铂处理后诱导黑色素细胞，但不诱导黑色素瘤细胞系。与 BRCA1、BRCA2、ATM 和 CHEK2 相关的转录本在顺铂处理后在黑色素瘤细胞系中的表达发生改变。在黑色素瘤肿瘤组织中，BRCA1 转录本的表达与不良预后相关，而 XPB 表达与太阳弹性蛋白水平相关。总之，这些发现为黑色素瘤 NER 缺陷的潜在机制提供了证据。
