PDF(Pubmed)
Abstract：
Ultraviolet (UV) light is the most pervasive environmental mutagen and the primary cause of skin cancer. Genome sequencing of melanomas and other skin cancers has revealed that the vast majority of somatic mutations in these tumors are cytosine-to-thymine (C>T) substitutions in dipyrimidine sequences, which, together with tandem CC>TT substitutions, comprise the canonical UV mutation \"signature\". These mutation classes are caused by DNA damage directly induced by UV absorption, namely cyclobutane pyrimidine dimers (CPDs) or 6-4 pyrimidine-pyrimidone photoproducts (6-4PP), which form between neighboring pyrimidine bases. However, many of the key driver mutations in melanoma do not fit this mutation signature, but instead are caused by T>A, T>C, C>A, or AC>TT substitutions, frequently occurring in non-dipyrimidine sequence contexts. This article describes recent studies indicating that UV light causes a more diverse spectrum of mutations than previously appreciated, including many of the mutation classes observed in melanoma driver mutations. Potential mechanisms for these diverse mutation signatures are discussed, including UV-induced pyrimidine-purine photoproducts and indirect DNA damage induced by UVA light. Finally, the article reviews recent findings indicating that human DNA polymerase eta normally suppresses these non-canonical UV mutation classes, which can potentially explain why canonical C>T substitutions predominate in human skin cancers.
摘要：
紫外线（UV）是最普遍的环境诱变剂和皮肤癌的主要原因。黑素瘤和其他皮肤癌的基因组测序表明，这些肿瘤中的绝大多数体细胞突变是双嘧啶序列中的胞嘧啶到胸腺嘧啶（C>T）取代，which,连同串联CC>TT替换，包括规范的紫外线突变“签名”。这些突变类型是由紫外线吸收直接诱导的DNA损伤引起的，即环丁烷嘧啶二聚体（CPD）或6-4嘧啶-嘧啶酮光产物（6-4PP），在相邻的嘧啶碱基之间形成。然而,黑色素瘤中的许多关键驱动突变不符合这种突变特征，而是由T>A引起的，T>C,C>A,或AC>TT替换，经常发生在非二嘧啶序列环境中。本文介绍了最近的研究表明，紫外线引起的突变比以前认识到的更多样化，包括在黑素瘤驱动突变中观察到的许多突变类别。讨论了这些不同突变特征的潜在机制，包括紫外线诱导的嘧啶嘌呤光产物和紫外线诱导的间接DNA损伤。最后,本文回顾了最近的发现，表明人类DNA聚合酶eta通常会抑制这些非规范的紫外线突变类别，这可能解释了为什么典型的C>T替换在人类皮肤癌中占主导地位。
