Huang et al. describe how the anaphase-promoting complex (APC/C) limits cell death and how this inhibition is relieved following DNA damage.
Bcl-2 family proteins such as Bax stimulate apoptosis by promoting the release of cytochrome c from mitochondria. A protein called modulator of apoptosis-1 (MOAP-1) helps activate Bax, but this protein is usually degraded too rapidly for it to induce apoptosis. In response to DNA damage, however, an E3 ubiquitin ligase called Trim39 enhances cell death by stabilizing MOAP-1, though how the ligase prevents MOAP-1 turnover is unclear.
Huang et al. realized that Trim39 is homologous to a Xenopus E3 enzyme called Xnf7, which inhibits the APC/C, a multisubunit ubiquitin ligase that promotes mitotic exit. Trim39 also inhibited the APC/C, so the researchers wondered whether MOAP-1 might be an APC/C substrate in the absence of an apoptotic signal. MOAP-1 was ubiquitinated by the APC/C, causing the pro-apoptotic protein to be degraded in G1 phase cell extracts. MOAP-1 ubiquitination and turnover was inhibited by wild-type Trim39 but not by a mutant version of the protein that lacked ligase activity.
MOAP-1 bound to the APC/C-activating protein Cdh1. Knocking down Cdh1 by RNAi increased MOAP-1 levels and facilitated Bax activation, enhancing cells’ susceptibility to death in response to DNA damage. Huang et al. now want to investigate how DNA damage activates Trim39 and to determine how the E3 ligase then inhibits the APC/C to stabilize MOAP-1 and promote apoptosis.
