Effect of small molecule eRF3 degraders on premature termination codon readthrough.
Effect of small molecule eRF3 degraders on premature termination codon readthrough.
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DOI：
10.1093/nar/gkab194
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发表时间：
2021-04-19
影响因子：
14.9
通讯作者：
Roberge M
中科院分区：
文献类型：
--
作者：
Baradaran-Heravi A;Balgi AD;Hosseini-Farahabadi S;Choi K;Has C;Roberge M
提前终止密码子（PTC）通读被认为是治疗无义突变引起的遗传病的潜在方法。高浓度的氨基糖苷类诱导低水平的PTC通读，但也引起严重的毒性。鉴定能够增强氨基糖苷类药物的PTC通读或降低其毒性的化合物是一个持续的挑战。在人类中，真核释放因子1（eRF 1）和3（eRF 3a或eRF 3b）的二元复合物介导翻译终止。它们还参与SURF（SMG 1-UPF 1-eRF 1-eRF 3）复合物组装，参与无义介导的mRNA衰变（NMD）。我们发现，PTC通读氨基糖苷G418是相当大的增强eRF 3a和eRF 3b siRNA和cereblon E3连接酶调节剂CC-885和CC-90009，诱导蛋白酶体降解的eRF 3a和eRF 3b。eRF 3降解还降低eRF 1水平，上调UPF 1，并选择性稳定携带无义突变的TP 53转录物，表明NMD抑制。CC-90009的毒性明显低于CC-885，并且在I型粘多糖样沉积症、晚期婴儿神经元蜡样质脂褐质沉积症、杜氏肌营养不良症和IDUA、TPP 1、DMD和COL 17 A1基因分别具有无义突变的交界性大疱性表皮病患者来源的细胞中，CC-90009与氨基糖苷类联合使用可增强PTC通读。CC-90009与庆大霉素或ELX-02等氨基糖苷类药物联合使用可能具有PTC通读治疗的潜力。
Premature termination codon (PTC) readthrough is considered a potential treatment for genetic diseases caused by nonsense mutations. High concentrations of aminoglycosides induce low levels of PTC readthrough but also elicit severe toxicity. Identifying compounds that enhance PTC readthrough by aminoglycosides or reduce their toxicity is a continuing challenge. In humans, a binary complex of eukaryotic release factors 1 (eRF1) and 3 (eRF3a or eRF3b) mediates translation termination. They also participate in the SURF (SMG1-UPF1-eRF1-eRF3) complex assembly involved in nonsense-mediated mRNA decay (NMD). We show that PTC readthrough by aminoglycoside G418 is considerably enhanced by eRF3a and eRF3b siRNAs and cereblon E3 ligase modulators CC-885 and CC-90009, which induce proteasomal degradation of eRF3a and eRF3b. eRF3 degradation also reduces eRF1 levels and upregulates UPF1 and selectively stabilizes TP53 transcripts bearing a nonsense mutation over WT, indicating NMD suppression. CC-90009 is considerably less toxic than CC-885 and it enhances PTC readthrough in combination with aminoglycosides in mucopolysaccharidosis type I-Hurler, late infantile neuronal ceroid lipofuscinosis, Duchenne muscular dystrophy and junctional epidermolysis bullosa patient-derived cells with nonsense mutations in the IDUA, TPP1, DMD and COL17A1 genes, respectively. Combination of CC-90009 with aminoglycosides such as gentamicin or ELX-02 may have potential for PTC readthrough therapy.