Poulos Rebecca C, Thoms Julie A I, Guan Yi Fang, Unnikrishnan Ashwin, Pimanda John E, Wong Jason W H
Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Australia, Sydney, NSW 2052, Australia.
Prince of Wales Clinical School and Lowy Cancer Research Center, UNSW Australia, Sydney, NSW 2052, Australia; Department of Haematology, Prince of Wales Hospital, Sydney, NSW 2052, Australia.
Cell Rep. 2016 Dec 13;17(11):2865-2872. doi: 10.1016/j.celrep.2016.11.055.
CTCF binding sites are frequently mutated in cancer, but how these mutations accumulate and whether they broadly perturb CTCF binding are not well understood. Here, we report that skin cancers exhibit a highly specific asymmetric mutation pattern within CTCF motifs attributable to ultraviolet irradiation and differential nucleotide excision repair (NER). CTCF binding site mutations form independently of replication timing and are enriched at sites of CTCF/cohesin complex binding, suggesting a role for cohesin in stabilizing CTCF-DNA binding and impairing NER. Performing CTCF ChIP-seq in a melanoma cell line, we show CTCF binding site mutations to be functional by demonstrating allele-specific reduction of CTCF binding to mutant alleles. While topologically associating domains with mutated CTCF anchors in melanoma contain differentially expressed cancer-associated genes, CTCF motif mutations appear generally under neutral selection. However, the frequency and potential functional impact of such mutations in melanoma highlights the need to consider their impact on cellular phenotype in individual genomes.
CTCF结合位点在癌症中经常发生突变，但这些突变如何积累以及它们是否广泛干扰CTCF结合尚不清楚。在这里，我们报告皮肤癌在CTCF基序内表现出高度特异性的不对称突变模式，这归因于紫外线照射和差异核苷酸切除修复（NER）。CTCF结合位点突变独立于复制时间形成，并在CTCF/黏连蛋白复合物结合位点富集，这表明黏连蛋白在稳定CTCF-DNA结合和损害NER中起作用。在黑色素瘤细胞系中进行CTCF ChIP-seq，我们通过证明CTCF与突变等位基因的结合存在等位基因特异性减少，表明CTCF结合位点突变具有功能。虽然黑色素瘤中具有突变CTCF锚定的拓扑相关结构域包含差异表达的癌症相关基因，但CTCF基序突变通常似乎处于中性选择之下。然而，黑色素瘤中此类突变的频率和潜在功能影响凸显了需要考虑它们对个体基因组中细胞表型的影响。
