- CCNF may also mean Canonical conjunctive normal form in Boolean algebra.
G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene. [5] [6]
G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene. [5] [6]
This gene encodes a member of the cyclin family. Cyclins are important regulators of cell cycle transitions through their ability to bind and activate cyclin-dependent protein kinases. This member also belongs to the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which are part of the ubiquitin-proteosome system (UPS). The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class and it was one of the first proteins in which the F-box motif was identified. [6]
CCNF gene was first discovered in 1994 by the Elledge laboratory while experimenting with Saccharomyces cerevisiae. [7] At the same time, the Frischauf laboratory also identified cyclin F as a new cyclin during their search for new candidate genes for polycystic kidney. [8] CCNF gene has 17 exons and is located at position 16p13.3 on the human chromosome. [7] Its protein, cyclin F, is made up of 786 amino acids and has a predicted molecular weight of 87 kDa. [7] Cyclin F is the main member of the F-box protein family, which has about 40 amino acid motif, forming the F-box. [7]
Cyclin F most closely resembles cyclin A in terms of sequence and expression patterns. [7] Moreover, it has additional shared features of cyclins, such as pEST region, protein quantity, localization, cell cycle-regulated mRNA, and ability to influence cell cycle and progression. [7] Cyclin F differs from other cyclins by its ability to monitor and regulate cell cycle without the need for cyclin-dependent kinases (CDKs). [9] Instead, the Pagano laboratory found that cyclin F is the substrate receptor of an SCF ubiquitin ligase that ubiquitinates and directly interacts with downstream targets, such as CP110 and RRM2, through its hydrophobic patch. [9]
Cyclin F mRNA is expressed in all human tissues, but at different quantities. [7] It is found most abundantly in the nucleus, and the quantity levels vary during the different stages of cell cycle. [7] Its expression pattern closely resembles the one from cyclin A. Cyclin F levels begin to rise during S phase and reaches its peak during G2. [7]
Cyclin F interacts with other proteins that are important for centrosomal duplication, gene transcription, and DNA synthesis, stability and repair.
RRM2 is a ribonucleotide reductase (RNR), an enzyme responsible for the conversion of ribonucleotides into dNTPs. dNTPs are essential for DNA synthesis during DNA replication and repair. [10] Cyclin F interacts with RRM2 to control the production of dNTPs in the cell to avoid genomic instability and frequency of mutations. [11]
Moreover, cyclin F located at the centrosomes are needed to regulate levels of CP110, a protein involved in centrosome duplication. [12] The regulation of CP110 during G2, through ubiquitin mediated proteolysis, helps to prevent mitotic aberrations. [12] by allowing only one centrosome replication per cell cycle.
NuSAP is a substrate of cyclin F that is involved in cell division. [13] It is a microtubule-associated protein that is required for the spindle assembly process. [14] Its function is to interact with microtubules and chromatin to create stabilization and cross-linking. [14] A lack of NuSAP has been linked with an increase in mutations due to impaired chromosome alignment during metaphase, while an excess of NuSAP leads to mitotic arrest and microtubule bundling. [15] Cyclin F help to control NUSAP abundance and is therefore essential to proper cell division.
SLBP is a protein that controls the mRNAs encoding canonical histones and H2A.X, thereby synchronizing histone metabolism with the cell cycle. In the G2 phase of the cell cycle, SLBP is degraded via cyclin F to control H2A.X levels after genotoxic stress. [16]
E2F1, E2F2, and E2F3A are the three canonical activators of the E2F family of transcription factors. During G2, cyclin F targets all three activator E2Fs for degradation, thereby turning off a main cell-cycle transcriptional engine. [17] [18]
CCNF mutations have more recently been associated to neurodegenerative diseases such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and co-morbid ALS-FTD. [19] [20] Whole-genome linkage analysis and genome sequencing identified CCNF to be linked to both familial and sporadic ALS patients. [19] In vitro and in vivo studies using ALS-linked mutations in CCNF were also carried out. It was found that certain CCNF mutations caused increased ubiquitylation activity of cyclin F [21] [22] [23] leading to abnormal ubiquitylation of proteins. [19] [24] In zebrafish, mutant CCNF fish showed motor neuron axonopathy and reduced motor response. [25] ALS/FTD patient induced pluripotent stem cell -derived motor neurons expressing endogenous mutant CCNF had increased ubiquitylated proteins, likely decreasing the available free ubiquitin pool, [21] which is essential for the protein degradation pathways that remove protein waste from motor neurons.
Cyclin F has a tumor suppressor role because normal expression is involved in cell cycle regulation by inducing G2 arrest and preventing mitosis. [26] Moreover, cyclin F through RRM2 and CP110 control centrosome duplication and reduce the frequency of genomic mutations. [9] So far, mutations in CCNF and increased RRM2 expression have been identified in several human cancers. [27]
Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.
Endoreduplication is replication of the nuclear genome in the absence of mitosis, which leads to elevated nuclear gene content and polyploidy. Endoreplication can be understood simply as a variant form of the mitotic cell cycle (G1-S-G2-M) in which mitosis is circumvented entirely, due to modulation of cyclin-dependent kinase (CDK) activity. Examples of endoreplication characterized in arthropod, mammalian, and plant species suggest that it is a universal developmental mechanism responsible for the differentiation and morphogenesis of cell types that fulfill an array of biological functions. While endoreplication is often limited to specific cell types in animals, it is considerably more widespread in plants, such that polyploidy can be detected in the majority of plant tissues.
Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.
p21Cip1, also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2. p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.
Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.
Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.
F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome.
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 gene.
Cullin 1, also known as CUL1, is a human protein and gene from cullin family. This protein plays an important role in protein degradation and protein ubiquitination.
RING-box protein 1 is a protein that in humans is encoded by the RBX1 gene.
Cullin-4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.
F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.
CDC34 is a gene that in humans encodes the protein Ubiquitin-conjugating enzyme E2 R1. This protein is a member of the ubiquitin-conjugating enzyme family, which catalyzes the covalent attachment of ubiquitin to other proteins.
F-box only protein 5 is a protein that in humans is encoded by the FBXO5 gene.
Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome. CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.
Ubiquitin-conjugating enzyme E2 C is a protein that in humans is encoded by the UBE2C gene.
βTrCP2 is a protein that in humans is encoded by the FBXW11 gene.
Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe. Wee1 has a molecular mass of 96 kDa and is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. Wee1 has homologues in many other organisms, including mammals.
Cdc4 is a substrate recognition component of the SCF ubiquitin ligase complex, which acts as a mediator of ubiquitin transfer to target proteins, leading to their subsequent degradation via the ubiquitin-proteasome pathway. Cdc4 targets primarily cell cycle regulators for proteolysis. It serves the function of an adaptor that brings target molecules to the core SCF complex. Cdc4 was originally identified in the model organism Saccharomyces cerevisiae. CDC4 gene function is required at G1/S and G2/M transitions during mitosis and at various stages during meiosis.
The G2-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms that ensures that cells don't initiate mitosis until damaged or incompletely replicated DNA is sufficiently repaired. Cells with a defective G2-M checkpoint will undergo apoptosis or death after cell division if they enter the M phase before repairing their DNA. The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.