Death takes a holiday

control may kick in even before a kinetochore is assembled. The mitotic checkpoint— controlled by Mad1, Mad2, Bub1, BubR1, and Bub3— delays anaphase by inhibiting APC until all kinetochores are properly attached to the spindle. Because inhibition of Mad2 leads to an accelerated mitosis and a precocious anaphase, it has been assumed that the checkpoint itself also regulates mitotic timing. But Mad2 does not represent all of its kinetochore partners. " The assumption was that all were required for the checkpoint, so all would be needed here too, " says Meraldi. But the authors found that only Mad2 and BubR1 delay anaphase even in cells with properly aligned chromosomes. The others monitor only gross problems with kinetochore attachments. Mad2 and BubR1 could be prevented from binding to kineto-chores and yet still regulate mitotic timing. In cells where mitosis requires nuclear breakdown, checkpoint proteins need to find their way to kinetochores after breakdown, leaving a window of time when the spindle checkpoint is not active. " APC could be held in check with this cytoplasmic function [of Mad2/BubR1], " says Meraldi. Now, the group needs to determine how this function is inactivated. ᭿ Death takes a holiday t times, the DIAP-1 anti-apoptotic protein is not what it seems. show that, in the fly ovary, this caspase inhibitor is needed for cell migration but not survival. Montell's group studies border cells in the fly egg chamber, which migrate to help establish the sperm entry site. Rac activity is needed for this; so to identify more players, the group screened for proteins that restore migration when Rac activity is reduced. They found DIAP-1. Although DIAP-1 is essential for cell survival in the embryo, its loss in the ovary caused migration defects but not cell death. Extra actin or profilin, presumably leading to increased actin polymer-ization, also compensated for the loss of Rac. DIAP-1 may also promote actin polymeriza-tion. To block apoptosis, DIAP-1 inhibits the fly caspase-9 homologue, called Dronc. Dronc is probably the DIAP-1 target in border cell migration as well, as reducing its activity suppressed the loss of Rac. Possible Dronc substrates include Rac and actin, which are cleaved by caspases during apoptosis, or profilin. The unexpected identification of DIAP-1 as a suppressor emphasizes the importance of random screens. " The whole point is to find something that you can't even imagine would be involved, " says Montell. Tumor cells that manage …