A cyclin without cyclin-dependent kinases: cyclin F controls genome stability through ubiquitin-mediated proteolysis

Abstract

Cell cycle transitions are driven by the periodic oscillations of cyclins, which bind and activate cyclin-dependent kinases (CDKs) to phosphorylate target substrates. Cyclin F uses a substrate recruitment strategy similar to that of the other cyclins, but its associated catalytic activity is substantially different. Indeed, cyclin F is the founding member of the F-box family of proteins, which are the substrate recognition subunits of Skp1-Cul1-F-box protein (SCF) ubiquitin ligase complexes. Here, we discuss cyclin F function and recently identified substrates of SCF(cyclin)(F) involved in deoxyribonucleotide triphosphate (dNTP) production, centrosome duplication, and spindle formation. We highlight the relevance of cyclin F in controlling genome stability through ubiquitin-mediated proteolysis and the implications for cancer development.

Fig. 1

Cyclin F contains three separate modules. A schematic representation of the three cyclin f modules: the pseudo-catalytic, substrate recruitment (cyclin box), regulatory modules. D'Angiolella et al.,

Fig. 2

Cyclin F uses a hydrophobic patch to bind the CY motif of target substrates. Cyclin F uses the hydrophobic patch in the cyclin domain to bind CY-containing substrates and through the F-box domain (pseudo-catalytic module) targets them for ubiquitylation and subsequent proteolysis. Cyclin B recruits substrates in a similar manner, but uses the CDK catalytic subunit to phosphorylate target substrates. D'Angiolella et al.,

Fig. 3

ATR-dependent regulation of RNR from yeast to mammals. RNR is is among the most well-conserved (from prokaryotes to eukaryotes) and highly-regulated enzymes. Spd1, Sml1, and cyclin F are three inhibitors of RNR in the fission yeast Schizosaccharomyces pombe, in the budding yeast Saccharomyces cerevisiae, and mammals, respectively. Whereas cyclin F promotes RRM2 degradation, Spd1 and Sml1 inhibit RNR by physical binding. In response to genotoxic stress, Cdt2 targets Spd1 for degradation,, while Ubr2/Rad6 promotes Sml1 proteolysis. All three events are dependent on ATR or ATR orthologs, (Rad3 and Mec1). D'Angiolella et al.,