The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner
The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner
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DOI：
10.3390/cancers12071717
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发表时间：
2020-07-01
期刊：
影响因子：
5.2
通讯作者：
Cordes, Nils
中科院分区：
文献类型：
--
作者：
Deville, Sara Sofia;Vehlow, Anne;Cordes, Nils
癌细胞的耐药是一个多方面的过程，其中DNA修复成为潜在的治疗靶点。DNA修复主要由核事件进行；然而，核外线索如何影响DNA损伤反应在很大程度上是未知的。在这里，我们使用基于rnai的高通量筛选在头颈部鳞状细胞癌（HNSCC）的三维培养细胞中发现了新的控制DNA修复的局点粘附蛋白，包括中间丝蛋白，synemin。我们证明synemin通过非同源末端连接修复关键调节DNA损伤反应。机制上，synemin通过其c端尾部结构域与DNA- pkcs形成蛋白质复合物，以atm依赖的方式决定该酶上游的DNA修复过程。我们的研究发现了中间丝蛋白（synemin）在DNA损伤反应中的关键功能，从根本上支持了细胞结构元件作为核事件共同调节因子的概念。
The treatment resistance of cancer cells is a multifaceted process in which DNA repair emerged as a potential therapeutic target. DNA repair is predominantly conducted by nuclear events; yet, how extra-nuclear cues impact the DNA damage response is largely unknown. Here, using a high-throughput RNAi-based screen in three-dimensionally-grown cell cultures of head and neck squamous cell carcinoma (HNSCC), we identified novel focal adhesion proteins controlling DNA repair, including the intermediate filament protein, synemin. We demonstrate that synemin critically regulates the DNA damage response by non-homologous end joining repair. Mechanistically, synemin forms a protein complex with DNA-PKcs through its C-terminal tail domain for determining DNA repair processes upstream of this enzyme in an ATM-dependent manner. Our study discovers a critical function of the intermediate filament protein, synemin in the DNA damage response, fundamentally supporting the concept of cytoarchitectural elements as co-regulators of nuclear events.