Ultraviolet radiation-induced DNA mutations are a primary environmental driver of melanoma. The reason for this very high level of unrepaired DNA lesions leading to these mutations is still poorly understood. The primary DNA repair mechanism for UV-induced lesions, that is, the nucleotide excision repair pathway, appears intact in most melanomas. We have previously reported a postreplication repair mechanism that is commonly defective in melanoma cell lines. Here we have used a genome-wide approach to identify the components of this postreplication repair mechanism. We have used differential transcript polysome loading to identify transcripts that are associated with UV response, and then functionally assessed these to identify novel components of this repair and cell cycle checkpoint network. We have identified multiple interaction nodes, including global genomic nucleotide excision repair and homologous recombination repair, and previously unexpected MASTL pathway, as components of the response. Finally, we have used bioinformatics to assess the contribution of dysregulated expression of these pathways to the UV signature mutation load of a large melanoma cohort. We show that dysregulation of the pathway, especially the DNA damage repair components, are significant contributors to UV mutation load, and that dysregulation of the MASTL pathway appears to be a significant contributor to high UV signature mutation load.

中文翻译：

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多个相互作用节点定义了对紫外线诱导的DNA损伤的复制后修复反应，该损伤在黑色素瘤中是缺陷的，并且与紫外线信号突变负载相关。

紫外线辐射诱导的DNA突变是黑色素瘤的主要环境驱动因素。导致这些突变的未修复DNA损伤水平很高的原因仍然知之甚少。在大多数黑素瘤中，紫外线引起的病变的主要DNA修复机制（即核苷酸切除修复途径）似乎完好无损。我们以前曾报道过复制后修复机制，通常在黑色素瘤细胞系中存在缺陷。在这里，我们已经使用了全基因组的方法来识别这种复制后修复机制的组件。我们已经使用差异转录多核糖体加载来识别与紫外线反应相关的转录本，然后在功能上评估这些转录本，以鉴定这种修复和细胞周期检查点网络的新组成部分。我们确定了多个交互节点，包括整体基因组核苷酸切除修复和同源重组修复，以及以前意想不到的MASTL途径，作为响应的组成部分。最后，我们使用生物信息学来评估这些途径表达失调对大型黑色素瘤人群的紫外线信号突变负荷的贡献。我们显示该通路的失调，尤其是DNA损伤修复组分，是造成UV突变负荷的重要因素，而MASTL通路的失调似乎是造成高UV标记突变负荷的重要因素。我们已经使用生物信息学来评估这些途径的表达失调对大型黑色素瘤人群的紫外线信号突变负荷的贡献。我们显示该通路的失调，特别是DNA损伤修复组分，是造成UV突变负荷的重要因素，而MASTL通路的失调似乎是造成高UV标记突变负荷的重要因素。我们已经使用生物信息学来评估这些途径的表达失调对大型黑色素瘤人群的紫外线信号突变负荷的贡献。我们显示该通路的失调，特别是DNA损伤修复组分，是造成UV突变负荷的重要因素，而MASTL通路的失调似乎是造成高UV标记突变负荷的重要因素。