Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
FEBS J. 2019 Dec;286(24):4951-4963. doi: 10.1111/febs.15008. Epub 2019 Aug 1.
Capicua (CIC) is a transcriptional repressor and functions downstream of the receptor tyrosine kinase (RTK) signaling pathway. Somatic mutations found in the HMG-box DNA binding domain in CIC have been implicated in several cancers such as oligodendroglioma, oligoastrocytoma, and adenocarcinoma. However, the molecular basis of the DNA binding of CIC and the effect of the somatic mutations found in cancers on DNA binding have not been investigated. Here, we report the crystal structure of the HMG-box domain of CIC complexed with its target DNA, the promoter of Ets Translocation Variant 5 (ETV5). The structure shows that the HMG-box domain has an L-shaped structure and recognizes the minor groove leading to DNA bending. Our structure combined with an electrophoretic mobility shift assay (EMSA) revealed that cancer-associated mutations in the HMG-box domain abrogate the interaction with DNA. These results provide the molecular insight into the DNA binding of CIC and reveal the effects of carcinogenic mutations on DNA binding.
CIC（Capicua）是一种转录抑制剂，其功能位于受体酪氨酸激酶（RTK）信号通路的下游。在 CIC 的 HMG 盒 DNA 结合结构域中发现的体细胞突变与几种癌症有关，如少突神经胶质瘤、少突星形细胞瘤和腺癌。然而，CIC 的 DNA 结合的分子基础以及在癌症中发现的体细胞突变对 DNA 结合的影响尚未得到研究。在这里，我们报告了 CIC 的 HMG 盒结构域与其靶 DNA（Ets 易位变体 5（ETV5）启动子）复合物的晶体结构。该结构表明，HMG 盒结构域具有 L 形结构，并识别导致 DNA 弯曲的小沟。我们的结构结合电泳迁移率变动分析（EMSA）表明，HMG 盒结构域中的癌症相关突变会破坏与 DNA 的相互作用。这些结果提供了对 CIC 的 DNA 结合的分子见解，并揭示了致癌突变对 DNA 结合的影响。
