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CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

Author

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  • Malgorzata Krajewska

    (Dana-Farber Cancer Institute and Boston Children’s Hospital
    Harvard Medical School)

  • Ruben Dries

    (Dana-Farber Cancer Institute and Boston Children’s Hospital
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Andrew V. Grassetti

    (Geisel School of Medicine at Dartmouth)

  • Sofia Dust

    (University of Bonn)

  • Yang Gao

    (Dana-Farber Cancer Institute and Boston Children’s Hospital
    Harvard Medical School)

  • Hao Huang

    (Dana-Farber Cancer Institute and Boston Children’s Hospital
    Harvard Medical School)

  • Bandana Sharma

    (Dana-Farber Cancer Institute and Boston Children’s Hospital)

  • Daniel S. Day

    (Massachusetts Institute of Technology)

  • Nicholas Kwiatkowski

    (Dana-Farber Cancer Institute)

  • Monica Pomaville

    (Dana-Farber Cancer Institute and Boston Children’s Hospital)

  • Oliver Dodd

    (Dana-Farber Cancer Institute and Boston Children’s Hospital)

  • Edmond Chipumuro

    (Dana-Farber Cancer Institute and Boston Children’s Hospital)

  • Tinghu Zhang

    (Dana-Farber Cancer Institute)

  • Arno L. Greenleaf

    (Duke University Medical Center)

  • Guo-Cheng Yuan

    (Dana-Farber Cancer Institute
    Harvard School of Public Health)

  • Nathanael S. Gray

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Richard A. Young

    (Massachusetts Institute of Technology)

  • Matthias Geyer

    (University of Bonn)

  • Scott A. Gerber

    (Geisel School of Medicine at Dartmouth)

  • Rani E. George

    (Dana-Farber Cancer Institute and Boston Children’s Hospital
    Harvard Medical School)

Abstract

Cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and selectively affects the expression of genes involved in the DNA damage response (DDR) and mRNA processing. Yet, the mechanisms underlying such selectivity remain unclear. Here we show that CDK12 inhibition in cancer cells lacking CDK12 mutations results in gene length-dependent elongation defects, inducing premature cleavage and polyadenylation (PCPA) and loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlates with an increased number of intronic polyadenylation sites, a feature especially prominent among DDR genes. Phosphoproteomic analysis indicated that CDK12 directly phosphorylates pre-mRNA processing factors, including those regulating PCPA. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition primarily due to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites.

Suggested Citation

  • Malgorzata Krajewska & Ruben Dries & Andrew V. Grassetti & Sofia Dust & Yang Gao & Hao Huang & Bandana Sharma & Daniel S. Day & Nicholas Kwiatkowski & Monica Pomaville & Oliver Dodd & Edmond Chipumuro, 2019. "CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09703-y
    DOI: 10.1038/s41467-019-09703-y
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    Cited by:

    1. Maria C. Tanzer & Isabell Bludau & Che A. Stafford & Veit Hornung & Matthias Mann, 2021. "Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. M. G. Filippone & D. Gaglio & R. Bonfanti & F. A. Tucci & E. Ceccacci & R. Pennisi & M. Bonanomi & G. Jodice & M. Tillhon & F. Montani & G. Bertalot & S. Freddi & M. Vecchi & A. Taglialatela & M. Roma, 2022. "CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Thomas G. Paulson & Patricia C. Galipeau & Kenji M. Oman & Carissa A. Sanchez & Mary K. Kuhner & Lucian P. Smith & Kevin Hadi & Minita Shah & Kanika Arora & Jennifer Shelton & Molly Johnson & Andre Co, 2022. "Somatic whole genome dynamics of precancer in Barrett’s esophagus reveals features associated with disease progression," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Xiaochuan Liu & Hao Chen & Zekun Li & Xiaoxiao Yang & Wen Jin & Yuting Wang & Jian Zheng & Long Li & Chenghao Xuan & Jiapei Yuan & Yang Yang, 2024. "InPACT: a computational method for accurate characterization of intronic polyadenylation from RNA sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Buki Kwon & Mervin M. Fansler & Neil D. Patel & Jihye Lee & Weirui Ma & Christine Mayr, 2022. "Enhancers regulate 3′ end processing activity to control expression of alternative 3′UTR isoforms," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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