Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control

Abstract

Cells respond to DNA damage by activating cell cycle checkpoints to delay proliferation and facilitate DNA repair. Here, to uncover new checkpoint regulators, we perform RNA interference screening targeting genes involved in ubiquitylation processes. We show that the F-box protein cyclin F plays an important role in checkpoint control following ionizing radiation. Cyclin F-depleted cells initiate checkpoint signalling after ionizing radiation, but fail to maintain G2 phase arrest and progress into mitosis prematurely. Importantly, cyclin F suppresses the B-Myb-driven transcriptional programme that promotes accumulation of crucial mitosis-promoting proteins. Cyclin F interacts with B-Myb via the cyclin box domain. This interaction is important to suppress cyclin A-mediated phosphorylation of B-Myb, a key step in B-Myb activation. In summary, we uncover a regulatory mechanism linking the F-box protein cyclin F with suppression of the B-Myb/cyclin A pathway to ensure a DNA damage-induced checkpoint response in G2.

MYBL2 is a Potential Prognostic Marker that Promotes Cell Proliferation in Gallbladder Cancer

“…The critical function of the checkpoint in the G2 phase is the inhibition of CDK activity‚ which drives the G2-to-M cell cycle transition to block entry into mitosis in the presence of damaged DNA. Based on the work reported here and in previous studies [12, 36, 37], The MuvB core sequentially recruits MYBL2 and then FoxM1 to promote the expression of G2/M cell cycle genes. The balance between the DREAM complex and the MYBL2-MuvB complex are frequently perturbed in several cancers.…”

F-box protein interactions with the hallmark pathways in cancer

“…NAUSP1 is degraded during S and G2 phases, but can also be degraded in response to UV-mediated DNA damage, although this is not catalysed by SCF(Fbxo1), indicating another protein regulates its response to DNA damage. Fbxo1 also regulates the checkpoint at G2 in response to ionising radiation in a non-canonical manner, possibly by competing with cyclin A/Cdk for binding to transcription factor (TF) B-Myb (56). This prevents the cyclin A/Cdk phosphorylation of B-Myb, thereby crippling its transactivation of genes like PLK1, cyclin B and cyclin A, and AurKA, which promote entry into mitosis.…”

Deregulation of F-box proteins and its consequence on cancer development, progression and metastasis

“…Cyclin F plays another role in cell cycle checkpoint control via the suppression of oncoprotein B-MYB [226], a transcriptional activator involved in cell cycle progression. Following IR, Cyclin F interacts with B-MYB through its cyclin box domain to prevent B-MYB phosphorylation by cyclin A-CDK [226].…”

“…Following IR, Cyclin F interacts with B-MYB through its cyclin box domain to prevent B-MYB phosphorylation by cyclin A-CDK [226]. Consequently, B-MYB is unable to promote G2 progression until DNA damage can be repaired.…”

“…Consequently, B-MYB is unable to promote G2 progression until DNA damage can be repaired. This ensures the preservation of the G2 checkpoint response following IR [226]. …”