Nucleosome positions establish an extended mutation signature in melanoma.
Nucleosome positions establish an extended mutation signature in melanoma.
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DOI：
10.1371/journal.pgen.1007823
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发表时间：
2018-11
期刊：
影响因子：
4.5
通讯作者：
Roberts SA
中科院分区：
文献类型：
--
作者：
Brown AJ;Mao P;Smerdon MJ;Wyrick JJ;Roberts SA
紫外线（UV）诱导的突变在皮肤癌基因组中分布不均匀，但造成这种异质性的分子机制尚未完全了解。在这里，我们评估了核小体结构如何影响人类黑色素瘤中紫外线诱导突变的位置。在强定位核小体内的皮肤黑色素瘤突变位置的分析揭示了突变密度的显著~10个碱基对（bp）振荡，峰出现在背对组蛋白八聚体的二核苷酸处。此外，在核小体二分体处的较高突变密度在构成核小体核心颗粒的147 bp DNA上产生了总体的“平移曲率”。这种周期性和曲率不能用核小体DNA中的序列偏差来解释。相反，我们的紫外线诱导的环丁烷嘧啶二聚体（CPD）的全基因组图谱表明，CPD的形成是在面向外的二核苷酸升高，反映了核小体结合的DNA内的突变密度的振荡。通过XR-seq测量的核苷酸切除修复（NER）活性与核小体的翻译设置相关的突变密度的曲率负相关。尽管无论染色质状态、组蛋白修饰和转录水平如何，突变的10 bp周期性在核小体中保持不变，但核心颗粒的总体突变密度和曲率随着转录水平的降低而增加。我们的观察结果表明，DNA的结构构象促进CPD形成在核小体内的特定位点，和空间位阻逐步限制病变修复对核小体二分体。这两种机制都在人类基因组中的强定位核小体内创建了独特的扩展突变签名。紫外线诱导的突变是丰富的，并在黑色素瘤基因组中不均匀分布。了解产生这种异质性的机制可能有助于破译哪些突变驱动癌症表型。虽然已知突变密度与大规模染色质致密化相关，但最近的研究表明，局部染色质结构以以前未检测到的方式影响突变分布。因此，我们研究了黑色素瘤突变在强定位核小体中的分布，我们观察到了显著的振荡和曲率模式。紫外线损伤的形成似乎是负责突变振荡，尽管发生在核小体核心颗粒的主动修复。然而，更多的CPD病变被删除的核小体的边缘附近，从而产生了一个整体的突变密度的平移曲率。
Ultraviolet (UV) light-induced mutations are unevenly distributed across skin cancer genomes, but the molecular mechanisms responsible for this heterogeneity are not fully understood. Here, we assessed how nucleosome structure impacts the positions of UV-induced mutations in human melanomas. Analysis of mutation positions from cutaneous melanomas within strongly positioned nucleosomes revealed a striking ~10 base pair (bp) oscillation in mutation density with peaks occurring at dinucleotides facing away from the histone octamer. Additionally, higher mutation density at the nucleosome dyad generated an overarching “translational curvature” across the 147 bp of DNA that constitutes the nucleosome core particle. This periodicity and curvature cannot be explained by sequence biases in nucleosomal DNA. Instead, our genome-wide map of UV-induced cyclobutane pyrimidine dimers (CPDs) indicates that CPD formation is elevated at outward facing dinucleotides, mirroring the oscillation of mutation density within nucleosome-bound DNA. Nucleotide excision repair (NER) activity, as measured by XR-seq, inversely correlated with the curvature of mutation density associated with the translational setting of the nucleosome. While the 10 bp periodicity of mutations is maintained across nucleosomes regardless of chromatin state, histone modifications, and transcription levels, overall mutation density and curvature across the core particle increased with lower transcription levels. Our observations suggest structural conformations of DNA promote CPD formation at specific sites within nucleosomes, and steric hindrance progressively limits lesion repair towards the nucleosome dyad. Both mechanisms create a unique extended mutation signature within strongly positioned nucleosomes across the human genome. UV-induced mutations are abundant and heterogeneously distributed across melanoma genomes. Understanding the mechanisms that produce this heterogeneity may help decipher which mutations drive the cancer phenotype. While it is known that mutation density correlates with chromatin compaction on a large scale, recent studies have suggested that local chromatin structure impacts mutation distribution in ways previously undetected. We therefore examined the distribution of melanoma mutations in strongly positioned nucleosomes where we observed a striking oscillatory and curvature pattern. UV lesion formation appeared to be responsible for mutation oscillation, despite active repair occurring in the nucleosome core particle. However, more CPD lesions are removed near the edges of nucleosomes, and thus generated an overall translational curvature in mutation density.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
12.3
作者：
Duan C;Huan Q;Chen X;Wu S;Carey LB;He X;Qian W
通讯作者：
Qian W
影响因子：
2.9
作者：
Liu, XQ;Mann, DB;Smerdon, MJ
通讯作者：
Smerdon, MJ
DOI：
10.1073/pnas.1706522114
发表时间：
2017-06-27
影响因子：
11.1
作者：
Hu, Jinchuan;Adebali, Ogun;Sancar, Aziz
通讯作者：
Sancar, Aziz
鉴定癌症类型的显着突变区域的鉴定突出了功能分子改变的丰富景观。
影响因子：
30.8
作者：
Araya CL;Cenik C;Reuter JA;Kiss G;Pande VS;Snyder MP;Greenleaf WJ
通讯作者：
Greenleaf WJ