Budden Timothy, Davey Ryan J, Vilain Ricardo E, Ashton Katie A, Braye Stephen G, Beveridge Natalie J, Bowden Nikola A
Hunter Medical Research Institute and Faculty of Health, University of Newcastle, Callaghan, NSW, Australia.
Melanoma Institute of Australia, Camperdown, NSW, Australia.
Oncotarget. 2016 Sep 20;7(38):60940-60953. doi: 10.18632/oncotarget.10902.
UVB exposure leads to DNA damage, which when unrepaired induces C>T transitions. These mutations are found throughout the melanoma genome, particularly in non-transcribed regions. The global genome repair (GGR) branch of nucleotide excision repair (NER) is responsible for repairing UV-induced DNA damage across non-transcribed and silent regions of the genome. This study aimed to examine the relationship between UVB and GGR in melanoma. DNA repair capacity and relative expression of NER in melanocytes and melanoma cell lines before and after treatment with UVB was quantified. Transcript expression from 196 melanomas was compared to clinical parameters including solar elastosis and whole transcriptome data collected. Melanoma cell lines showed significantly reduced DNA repair when compared to melanocytes, most significantly in the S phase of the cell cycle. Expression of GGR components XPC, DDB1 and DDB2 was significantly lower in melanoma after UVB. In the melanoma tumours, XPC expression correlated with age of diagnosis and low XPC conferred significantly poorer survival. The same trend was seen in the TCGA melanoma dataset. Reduced GGR in melanoma may contribute to the UV mutation spectrum of the melanoma genome and adds further to the growing evidence of the link between UV, NER and melanoma.
紫外线B（UVB）照射会导致DNA损伤，若损伤未得到修复，会诱导胞嘧啶（C）向胸腺嘧啶（T）的转变。这些突变存在于整个黑色素瘤基因组中，尤其在非转录区域。核苷酸切除修复（NER）的全局基因组修复（GGR）分支负责修复基因组非转录和沉默区域的紫外线诱导的DNA损伤。本研究旨在探讨黑色素瘤中UVB与GGR之间的关系。对黑色素细胞和黑色素瘤细胞系在UVB处理前后的DNA修复能力及NER的相对表达进行了定量分析。将196例黑色素瘤的转录本表达与包括日光性弹力组织变性在内的临床参数以及收集的全转录组数据进行了比较。与黑色素细胞相比，黑色素瘤细胞系的DNA修复能力显著降低，在细胞周期的S期最为明显。UVB照射后，黑色素瘤中GGR成分XPC、DDB1和DDB2的表达显著降低。在黑色素瘤肿瘤中，XPC表达与诊断年龄相关，XPC表达水平低的患者生存率显著较差。在癌症基因组图谱（TCGA）黑色素瘤数据集中也观察到了相同的趋势。黑色素瘤中GGR的降低可能导致黑色素瘤基因组的紫外线突变谱，并进一步增加了紫外线、NER与黑色素瘤之间联系的证据。
