The RNA polymerase II (RNAPII) C-terminal domain kinase, CDK12, regulates genome stability, expression of DNA repair genes, and cancer cell resistance to chemotherapy and immunotherapy. In addition to its role in mRNA biosynthesis of DNA repair genes, we show here that CDK12 phosphorylates the mRNA 5' cap-binding repressor, 4E-BP1, to promote translation of mTORC1-dependent mRNAs. In particular, we found that phosphorylation of 4E-BP1 by mTORC1 (T37 and T46) facilitates subsequent CDK12 phosphorylation at two Ser-Pro sites (S65 and T70) that control the exchange of 4E-BP1 with eIF4G at the 5' cap of CHK1 and other target mRNAs. RNA immunoprecipitation coupled with deep sequencing (RIP-seq) revealed that CDK12 regulates release of 4E-BP1, and binding of eIF4G, to many mTORC1 target mRNAs, including those needed for MYC transformation. Genome-wide ribosome profiling (Ribo-seq) further identified specific CDK12 "translation-only" target mRNAs, including many mTORC1 target mRNAs as well as many subunits of mitotic and centromere/centrosome complexes. Accordingly, confocal imaging analyses revealed severe chromosome misalignment, bridging, and segregation defects in cells deprived of CDK12 or CCNK. We conclude that the nuclear RNAPII-CTD kinase CDK12 cooperates with mTORC1, and controls a specialized translation network that is essential for mitotic chromosome stability.

中文翻译：

---

CDK12使4E-BP1磷酸化，从而实现mTORC1依赖性翻译和有丝分裂基因组稳定性。

RNA聚合酶II（RNAPII）C端域激酶CDK12调节基因组稳定性，DNA修复基因的表达以及癌细胞对化学疗法和免疫疗法的抵抗力。除了其在DNA修复基因的mRNA生物合成中的作用外，我们在这里还显示CDK12使mRNA 5'帽结合阻遏物4E-BP1磷酸化，从而促进mTORC1依赖性mRNA的翻译。特别是，我们发现mTORC1（T37和T46）对4E-BP1的磷酸化促进了随后在两个Ser-Pro位点（S65和T70）上的CDK12磷酸化，从而控制了CHK1 5'帽上4E-BP1与eIF4G的交换。和其他目标mRNA。RNA免疫沉淀与深度测序（RIP-seq）结合显示CDK12调节4E-BP1的释放以及eIF4G与许多mTORC1目标mRNA的结合，包括MYC转化所需的mRNA。全基因组的核糖体谱（Ribo-seq）进一步鉴定了特定的CDK12“仅翻译”靶mRNA，包括许多mTORC1靶mRNA以及有丝分裂和着丝粒/着丝粒复合体的许多亚基。因此，共聚焦成像分析显示缺乏CDK12或CCNK的细胞中存在严重的染色体错位，桥联和分离缺陷。我们得出结论，核RNAPII-CTD激​​酶CDK12与mTORC1协同作用，并控制有丝分裂染色体稳定性必不可少的专门翻译网络。缺乏CDK12或CCNK的细胞中的桥连和分离缺陷。我们得出的结论是，核RNAPII-CTD激​​酶CDK12与mTORC1合作，并控制有丝分裂染色体稳定性必不可少的专门翻译网络。缺乏CDK12或CCNK的细胞中的桥连和分离缺陷。我们得出结论，核RNAPII-CTD激​​酶CDK12与mTORC1协同作用，并控制有丝分裂染色体稳定性必不可少的专门翻译网络。