CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability

Genes Dev. 2019 Apr 1;33(7-8):418-435. doi: 10.1101/gad.322339.118. Epub 2019 Feb 28.


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.

Keywords: 4E-BP1; CDK12; RNAPII CTD kinase; chromosome misalignment; genome stability; mTORC1; translation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Checkpoint Kinase 1 / genetics*
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Cyclins / genetics
  • Cyclins / metabolism
  • Eukaryotic Initiation Factor-4G / metabolism
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genomic Instability / genetics*
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mitosis / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / genetics
  • Protein Binding / genetics


  • Adaptor Proteins, Signal Transducing
  • CCNK protein, human
  • Cell Cycle Proteins
  • Cyclins
  • EIF4EBP1 protein, human
  • EIF4G1 protein, human
  • Eukaryotic Initiation Factor-4G
  • Phosphoproteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Mechanistic Target of Rapamycin Complex 1
  • CDK12 protein, human
  • Cyclin-Dependent Kinases