FZR1
Function
Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. The APC/C remains active in degrading substrates to ensure that positive regulators of the cell cycle do not accumulate prematurely. At the G1/S transition FZR1 is phosphorylated, leading to its dissociation from the APC/C. Following DNA damage, it is required for the G2 DNA damage checkpoint: its dephosphorylation and reassociation with the APC/C leads to the ubiquitination of PLK1, preventing entry into mitosis. Acts as an adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, may play a role in DNA damage response, favoring DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:25349192).
Involvement in disease
Developmental and epileptic encephalopathy 109
DEE109
A form of epileptic encephalopathy, a heterogeneous group of early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE109 is an autosomal dominant form characterized by the onset of various types of seizures in the first months or years of life.
None
The disease is caused by variants affecting the gene represented in this entry.
Pathway
Protein modification; protein ubiquitination.
Post-translational modifications
Acetylated. Deacetylated by SIRT2 at Lys-69 and Lys-159; deacetylation enhances the interaction of FZR1 with CDC27, leading to activation of anaphase promoting complex/cyclosome (APC/C).
Following DNA damage, it is dephosphorylated by CDC14B in G2 phase, leading to its reassociation with the APC/C, and allowing an efficient G2 DNA damage checkpoint (PubMed:18662541). Phosphorylated by MAK (PubMed:21986944).
Ubiquitinated by the SCF(CCNF) E3 ubiquitin-protein ligase complex; leading to its degradation by the proteasome.
Sequence Similarities
Belongs to the WD repeat CDC20/Fizzy family.
Tissue Specificity
Isoform 2 is expressed at high levels in heart, liver, spleen and some cancer cell lines whereas isoform 3 is expressed only at low levels in these tissues.
Cellular localization
- Isoform 2
- Nucleus
- Isoform 3
- Cytoplasm
Alternative names
CDH1, FYR, FZR, KIAA1242, FZR1, Fizzy-related protein homolog, Fzr, CDC20-like protein 1, Cdh1/Hct1 homolog, hCDH1