Putting mitosis in reverse

Cells exiting mitosis are able to undo their work and return to metaphase if cyclin B is preserved, as revealed by a new study from Tamara Potapova, Gary Gorbsky (Oklahoma Medical Research Foundation, Oklahoma City, OK), and colleagues.

The destruction of cyclin B at anaphase, and the resulting inactivation of Cdk1, ushers in mitotic exit and cytokinesis. By tinkering with these mitotic regulators, Gorbsky's group reversed mitotic exit in vertebrate cells.

The authors first inhibited proteasome activity to preserve cyclin B at anaphase onset, creating a mitotic stall. They then forced these cells into cytokinesis by inhibiting Cdk1 activity. If they then withdrew the Cdk1 inhibitor, the cells reverted back into mitosis. The cleavage furrow opened, the nuclear envelope dissolved, chromatin recondensed, and the mitotic spindle reformed and recaptured the chromosomes.

Cyclin B is not the whole story, however. “Clearly,” says Gorbsky, “cyclin B is not the only thing, because it's not reversible if we wait too long.” Another Cdk1 inhibitor might come into play later on, as Sic1 does in budding yeast. “Now that we have control of the first arrow of directionality, we can look at what's downstream of that.”

When Tim Hunt first identified cyclin and its periodic destruction, the notion that cells would repeatedly make and destroy a protein to control its activity was rather shocking. But by the late 1980s, when it was shown that nondegradable cyclin prevented mitotic exit, the idea that proteolysis provides directionality in mitosis no longer seemed so far fetched.

“Some people, perhaps rightly so, just accepted the notion that protein degradation makes [mitosis] irreversible,” says Gorbsky. “We just figured out that we could look at that. It could have turned out differently, if we couldn't reverse it.”

Protein degradation uses up a lot of energy, but it is apparently preferable to a cheaper, sloppier mechanism of directionality. “Bad things [such as premature centrosome splitting] can happen during mitosis,” says Gorbsky. “So reversing back into it is really not a good idea,” as even the reversal process itself might be error prone.

Reference: