APC/C regulation via CDH1-MAD2L2 interaction

Correct progression through mitosis is regulated by the Anaphase-Promoting Complex/Cyclosome (APC/C). The APC/C is an essential mitotic E3 ubiquitin ligase, controlling the accuracy of mitosis and the G1 phase. It has two activators, CDC20 and CDH1, which are also APC/C substrates. MAD2L2 also known as REV7, a central protein in the DNA damage tolerance pathway, was recently shown to participate in APC/C regulation. MAD2L2 binds CDH1 and prevents its premature binding to the APC/C. At the onset of anaphase, MAD2L2 is rapidly degraded by APC/C^CDC20, releasing CDH1 to bind and activate the APC/C. Loss of MAD2L2 leads to premature association of CDH1 with the APC/C and unscheduled destruction of APC/C^CDH1 substrates, causing accelerated mitosis exhibiting frequent mitotic aberrations. Thus, MAD2L2 plays an important role in safeguarding the switch between APC/C^CDC20 and APC/C^CDH1 during the metaphase-to-anaphase transition, thereby contributing to mitotic fidelity. Our goal is deepen our understanding of the MAD2L2-CDH1 complex and its regulation and influence on the APC/C. We present here in vitro and in vivo mapping of the MAD2L2 and CDH1 interaction, suggesting that both the conserved C-BOX on CDH1 and the CDH1 phosphorylation state are responsible for MAD2L2-CDH1 complex generation and stability. Understanding the mechanism of action of the MAD2L2-CDH1 complex and its effect on APC/C activity is important for dissecting the different roles of MAD2L2, as well as for developing targeted therapeutic agents designed to manipulate either APC/C activation or the DNA damage response.