| FZR1, also known as CDH1, is a WD-repeat–containing coactivator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. It acts as a substrate-selective adapter, linking APC/C activity to the temporal regulation of cyclins, mitotic regulators, and DNA damage–response factors during mitosis, G1, and the G2 checkpoint. FZR1 contains multiple WD40 repeats forming a β-propeller domain that recognizes degron motifs in substrates, and its N-terminal regulatory sites are phosphorylated by various kinases to modulate its interaction and activity with APC/C throughout the cell cycle. FZR1 binds the APC/C core in late mitosis and G1, directing ubiquitination of substrates such as mitotic cyclins, Aurora kinase A, PLK1, Skp2, and CtIP/RBBP8. This prevents premature accumulation of positive cell-cycle regulators, maintains low CDK activity in G1, and influences the choice between non-homologous end joining and homologous recombination during DNA double-strand break repair. Loss of FZR1 function in human and mouse somatic cells shortens G1, prolongs S phase, and leads to DNA damage accumulation and impaired proliferation without blocking mitotic exit, indicating that APC/C^FZR1 activity is dispensable for completion of mitosis but required for proper G1 control and efficient DNA replication. FZR1 also regulates the timing of meiosis I spindle assembly, supports maintenance of prophase I arrest, and prevents chromosome nondisjunction by targeting specific meiotic regulators for degradation; FZR1 insufficiency accelerates meiosis I and increases segregation errors. At the G2 DNA-damage checkpoint, FZR1 is dephosphorylated and reassociates with APC/C, promoting PLK1 ubiquitination and restraining mitotic entry, and, through CtIP turnover, participates in pathway choice for double-strand break repair and checkpoint enforcement. FZR1 regulates quiescence and self-renewal in hematopoietic stem cells by promoting ubiquitination of RUNX1 at defined lysines; FZR1 insufficiency leads to RUNX1 accumulation, disturbed quiescence, and altered stem-cell homeostasis. In cancer signaling, APC/C^FZR1 targets BRAF for degradation and restricts MAPK pathway output, with reduced FZR1 activity being associated with enhanced BRAF signaling and increased tumorigenic potential in melanoma models. |
