Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis
Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis
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DOI：
10.15252/embj.201796717
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发表时间：
2017-10-02
期刊：
影响因子：
11.4
通讯作者：
Morrison, Ashby J.
中科院分区：
文献类型：
--
作者：
Garcia-Nieto, Pablo E.;Schwartz, Erin K.;Morrison, Ashby J.
许多散发性癌症的发展是由接触致癌物直接引起的。致癌物通过制造DNA损伤（即加合物）诱发恶性肿瘤，如果不加以修复，这些损伤可导致突变。尽管有这些知识，但对获得DNA损伤的易感性调节的研究却非常少。在这项研究中，我们提出了第一个由紫外线（UV）辐射引起的DNA损伤的定量人类全基因组图谱，紫外线是阳光中普遍存在的致癌物质，可导致皮肤癌。值得注意的是，原代细胞基因组中致癌物易感性的模式显著反映了恶性黑色素瘤的突变频率。令人惊讶的是，dna可接近的常染色质受到紫外线的保护，而核周围层相关的异染色质则是脆弱的。许多癌症驱动基因在致癌物易感性方面具有内在的增加，包括在黑色素瘤中突变频率最高的BRAF癌基因。这些发现提供了癌变早期DNA损伤的全基因组快照。此外，他们确定致癌物易感性是基因组不稳定的一个来源，这是由核结构调节的，反映了癌症中的突变。
The development of many sporadic cancers is directly initiated by carcinogen exposure. Carcinogens induce malignancies by creating DNA lesions (i.e., adducts) that can result in mutations if left unrepaired. Despite this knowledge, there has been remarkably little investigation into the regulation of susceptibility to acquire DNA lesions. In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as an origin of genome instability that is regulated by nuclear architecture and mirrors mutagenesis in cancer.