PT  - JOURNAL ARTICLE
AU  - Kamila Burdova
AU  - Hongbin Yang
AU  - Roberta Faedda
AU  - Samuel Hume
AU  - Daniel Ebner
AU  - Benedikt M Kessler
AU  - Iolanda Vendrell
AU  - David H Drewry
AU  - Carrow I Wells
AU  - Stephanie B Hatch
AU  - Vincenzo D’Angiolella
TI  - Cyclin F-Chk1 synthetic lethality mediated by E2F1 degradation
AID  - 10.1101/509810
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 509810
4099  - http://biorxiv.org/content/early/2019/01/02/509810.short
4100  - http://biorxiv.org/content/early/2019/01/02/509810.full
AB  - Cyclins are central engines of cell cycle progression when partnered with Cyclin Dependent Kinases (CDKs). Among the different cyclins controlling cell cycle progression, cyclin F does not partner with a CDK, but forms an E3 ubiquitin ligase, assembling through the F-box domain, an Skp1-Cul1-F-box (SCF) module. Although multiple 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 cells with more than 200 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. The DNA replication catastrophe depends on the accumulation of E2F1 in cyclin F depleted cells. We observe that SCFcyclin F promotes E2F1 degradation after Chk1 inhibitors in a CDK dependent manner. Thus, Cyclin F restricts E2F1 activity during 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.