E2F1 proteolysis via SCF‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition

• Kamila Burdova ^[1] ; Hongbin Yang ^[1] ; Roberta Faedda ^[1] ; Samuel Hume ^[1] ; Jagat Chauhan ^[3] ; Daniel Ebner ^[1] ; Benedikt M Kessler ^[1] ; Iolanda Vendrell ^[1] ; David H Drewry ^[2] ; Carrow I Wells ^[2] ; Stephanie B Hatch ^[1] ; Grigory L Dianov ^[4] ; Francesca M Buffa ^[1] ; Vincenzo D'Angiolella ^[1]
  1. [1] University of Oxford

     University of Oxford

     Oxford District, Reino Unido

     
  2. [2] University of North Carolina at Chapel Hill

     University of North Carolina at Chapel Hill

     Township of Chapel Hill, Estados Unidos

     
  3. [3] 2 Nuffield Department of Clinical Medicine Ludwig Institute for Cancer Research University of Oxford Headington, Oxford UK
  4. [4] 1 Department of Oncology Medical Research Council Institute for Radiation Oncology University of Oxford Oxford UK; 5 Institute of Cytology and Genetics Russian Academy of Sciences Novosibirsk Russian Federation; 6 Novosibirsk State University Novosibirsk Russian Federation

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 20, 2019
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • Cyclins are central engines of cell cycle progression in conjunction with cyclin‐dependent kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but instead forms via its F‐box domain an SCF (Skp1‐Cul1‐F‐box)‐type E3 ubiquitin ligase module. Although various substrates of cyclin F have been identified, the vulnerabilities of cells lacking cyclin F are not known. Thus, we assessed viability of cells lacking cyclin F upon challenging them with more than 180 different kinase inhibitors. The screen revealed a striking synthetic lethality between Chk1 inhibition and cyclin F loss. Chk1 inhibition in cells lacking cyclin F leads to DNA replication catastrophe. Replication catastrophe depends on accumulation of the transcription factor E2F1 in cyclin F‐depleted cells. We find that SCF‐cyclin F controls E2F1 ubiquitylation and degradation during the G2/M phase of the cell cycle and upon challenging cells with Chk1 inhibitors. Thus, Cyclin F restricts E2F1 activity during the cell cycle and upon checkpoint inhibition to prevent DNA replication stress. Our findings pave the way for patient selection in the clinical use of checkpoint inhibitors.