# The Less Known Cyclins--Uncovered
## 3 Cyclin F  
Cyclin F with a molecular weight of 87 kDa is the largest cyclin. It is a cell cycle protein that in humans is encoded by the CCNF gene located in position 16p13.3. It was first identified in 1994 by [PERSON] et al., 1994 [20] and isolated as a suppressor of the G1/S phase transition deficiency of Saccharomyces cerevisiae CDC4 mutant. Cyclin F is the closest relative to the mitotic cyclins: A and B in terms of expression and structure [20; 21]. It also has features common to all cyclins, such as richness in proline, glutamic acid, serine and threonine (PEST) region, the abundance of protein, mRNA level dependent on cell cycle stage and ability to control the cell cycle progression [22]. Cyclin F is expressed in all human tissues at different concentrations depending on the cell cycle stage. In most cells, it shows subcellular localization, mainly in the nucleus (in the S and G2 phases), while in the others occurs only in the cytoplasm (mainly in the G2 phase) [20]. The pattern of expression is very similar to cyclin A. The level of cyclin F begins to increase in the S phase and reaches its peak during the G2 phase. However, it does not bind or activate any of the known Cdks. Cyclin F also differs from other cyclins by its ability to monitor and regulate the cell cycle even without activation [23]. Cyclin F is a unique cyclin because it contains not only the cyclin domain but also the F-box region. This domain is necessary for the binding of S-phase kinase-associated protein 1 (Skp1). It is the component of the ubiquitin ligase protein machinery Skp1-Cull-F-box (SCF). Skp1 also binds Cullin 1 (Cull1) and RING-box protein 1 (RBX1) to assemble a functional SCF complex. Moreover, RBX1 recruits regulatory protein E2 (E2) for the ubiquitination of target substrates. While other cyclins use the catalytic subunit of Cdk to phosphorylate target substrates, cyclin F uses the F-box domain to promote the ubiquitination of target substrates [22; 23]. In normal cells, cyclin F interacts with enzymes important for the synthesis, stability and repair of DNA. [PERSON] et al., 2013 [22] showed that cyclin F performs important functions in controlling centrosome duplication and prevents genomic instability by promoting the degradation of centriolar coiled-coil protein of 110 kDa (CP110) and ribonucleoside-diphosphate reductase subunit M2 (RRM2). Incorrect centrosome duplication and chromosome aberration contribute to the formation of tumors. As CP110 promotes duplication of centrosomes, cyclin F prevents genomic instability by ensuring that during every cell cycle only a single centrosome duplication event occurs. CP110 proteolysis by SCF with the participation of ubiquitin is crucial for maintaining centrosome homeostasis. sis and mitotic fidelity [24]. Another target for SCF is RRM2, which is a ribonucleotide reductase (RNR) subunit that allows the conversion of ribonucleotides to dNTP, which are then used in DNA synthesis and repair processes. A balanced pool of dNTP is one of the determinants of the replication accuracy, while an increase in their production is necessary for the process of DNA repair (Figure 2). This suggests that cyclin F helps to maintain genome integrity through modulation of RRM2 availability [2; 22]. Failure of cyclin F-dependent RRM2 degradation leads to an imbalance in the dNTP pool and increases the frequency of genomic mutations [25]. As was confirmed by [PERSON] et al., 2012 [23] RRM2 overexpression increases the probability of lung cancer occurrence in mice. Moreover, elevated RRM2 level is associated with poor prognosis in ovarian, liver, colorectal and breast cancer [23]. The third substrate of cyclin F is nucleolar and spindle-associated protein 1 (NuSAP). It belongs to the family of microtubule-associated proteins and is required for the spindle assembly process, where its main function is to interact with microtubules and chromatin to ensure stabilization and cross-linking [26].