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= Fizzy (Fzy) = The cell cycle regulation protein fizzy (fzy) is found in Drosophila melanogaster, and is a homolog of the CDC20 (cell division cycle) protein in Saccharomyces cerevisiae. The fzy protein is responsible for the proteolysis, the breakdown into amino acids, of cyclin A and cyclin B during cell division cycle transitions. Additionally, fzy helps microtubules take on correct spindle formations for division.

Discovery
The fizzy gene was first precisely mapped by Iain A. Dawson, Siegfried Roth, and Spyros Artavanis-Tsakonas in 1995 using chromosomal deficiencies and by screening cDNA libraries. After identifying the exact gene, the researchers were able to perform a germline transformation of their 2.5 kb fzy fragment.

Regulation of Cyclin
Fizzy is essential in regulating cell cycle division in Drosophila melanogaster. The cell cycle is carefully regulated by cell cycle checkpoints. One of the cell-cycle checkpoints occurs during the metaphase-anaphase transition, which is controlled by cyclin B degradation. Cyclins are regulatory proteins that control the progression of cells through the cell cycle. They form cyclin-dependent kinase (CDK) complexes, which phosphorylate various target proteins to push the cell cycle forward. The degradation of cyclins is essential for the cell to transition from one phase of the cycle to the next. For example, the degradation of cyclin B is crucial for the progression from metaphase to anaphase in mitosis. Proper cyclin degradation ensures that the cell cycle does not proceed unchecked, which is important in preventing uncontrolled cell proliferation – a hallmark of cancer. By degrading cyclins at the right time, cells can avoid entering the next phase of the cycle prematurely or inappropriately. The fzy protein is essential in properly regulating cyclin at this crucial cell checkpoint.

Fzy, in conjuction with fizzy-related, are able to activate the anaphase-promoting complex, triggering the ubiquitination of cyclin. It is believed that the recognition of cyclin by the ubiquitin-conjugating complex is possibly regulated by the M-phase promoting factor.

Spindle Formation Facilitation
Additionally, proper spindle formation is critical for passing the metaphase-anaphase cell division checkpoint. Fizzy, in the anaphase-promoting complex, help regulate the formation of astral microtubules, a specific type of microtubules only present before and during mitosis. These microtubules come from the center of the centrosome, forming a star-shaped array to assist in chromosome segregation. The astral microtubules are responsible for generating spindle asymmetry, daughter-cell-size asymmetry, and distinct sibling fates, all factors that help create diversity in cell types.

Interaction with Securin:
Securin is an important regulation protein that inhibits separase until the metaphase-anaphase cell cycle transition. Securin degradation is catalyzed by fizzy and also fizzy-related proteins. The fzy and fzr activate the anaphase promoting complex to ubiquitinate securin. The degradation of securin can be signaled by two conserved motifs: the RXXL destruction box and a KEN box. When securin is not properly degraded, chromosomes do not separate properly. For example, in an experiment by Zur and Brandeis 2001, when a non-degradable securin mutant was added to cells, cells remained connected by thin threads of chromatin, indicative of one or more non-separated chromosomes.

WD40-repeat proteins and Fizzy Related (FZR) Proteins
Fzr proteins are also in the WD40-repeat proteins family. This family of proteins acts as scaffolds to facilitate interactions in multi-protein complexes. CDC20p and HCT1p/CDH1p in Saccharomyces cerevisiae and fizzy and fizzy-related in Drosophila melanogaster are proteins in the WD40 family. Unlike fzy, which is only found in Drosophila, fzr are present in Xenopus, Drosophila, and in mammals.

The fizzy-related (fzr) proteins bind to Cdh1, and work with fzy and Cdc20. They also bind and activate cdk1 for degradation during mitosis and G1. Overall, fzr are necessary in properly regulating G1 and M arrest/progression in differentiating cells.

Mutations
Mutations in the fizzy gene locus arrest cells in metaphase. The cell requires maternally supplied fzy to facilitate the proper division of nuclei. In embryos with a faulty fzy gene, cells fail to divide and cannot differentiate. The embryo then dies.

In female Drosophila, there is a Cdc20/Cdh1 homologue called cortex. Without cortex and fizzy, germ cells will arrest in meiosis I and die.

External links section
https://flybase.org/reports/FBgn0001086.html