New cell cycle complexities

New findings are calling into question a long-held theory for how a dividing cell decides to stop the process of mitosis and restart the cell cycle.

Chromosomes (blue) and mitotic
spindle (green) during cell division
Image: Oak Ridge Nat'l Lab, via Wikipedia

Science textbooks have long claimed that what drives this decision is the breakdown of cell cycle-related proteins called cyclins at the end of the cycle's mitosis phase, but a linkurl:study published online;https://www.nature.com/nature/journal/vaop/ncurrent/full/nature07984.html this week in Nature suggests things may not be that simple. Instead, the authors propose cyclin levels regulate a genetic feedback mechanism that makes sure cell cycle stages happen in the right order. Two of the study's authors "have been championing this view for years now, and it's [good] to see the experimental test of this view pan out so nicely," linkurl:James Ferrell,;https://www.stanford.edu/group/ferrelllab/ a molecular and systems biologist at Stanford University who was not involved in the research, wrote in an email to The Scientist. One of the key elements of the cell cycle is that it only goes in one direction. During the cycle's interphase, DNA is replicated and the cell grows in order to be able to divide. Then, during the mitosis phase, the cell -- and its genetic material -- divides into two daughter cells. After a short resting phase, the cycle starts again. "Mitotic exit" -- the transition out of mitosis and back to the cycle's start -- "is an especially important transition," said linkurl:Frank Uhlmann,;https://science.cancerresearchuk.org/research/loc/london/lifch/uhlmannf/ a cell biologist Cancer Research UK in London and main author on the study. Because the DNA is in no shape to divide again, "under no circumstances do you want to go back into mitosis." Since the discovery of key cell cycle regulating molecules by Leland Hartwell, Tim Hunt, and Paul Nurse (who won the 2001 linkurl:Nobel Prize in Physiology or Medicine;https://nobelprize.org/nobel_prizes/medicine/laureates/2001/index.html for their contribution), biologists have believed that it's the destruction of cyclins, which are present in high levels during mitosis and undergo proteolysis after chromosomes complete their segregation, that makes mitotic exit irreversible. The idea was that since protein destruction is an irreversible step, the same would be true for mitotic exit. But some researchers now say that this model may be based on a flawed assumption. "While it's true that many people seem to think that the 'irreversibility' of proteolyis causes mitotic exit to be irreversible, in fact proteolysis is not irreversible," explained Ferrell. "Proteins can be replaced by translation on a time scale of tens of minutes. Protein degradation, like protein synthesis, is perfectly reversible under normal circumstances." A collaboration between his group and Hungarian mathematical biologists, also coauthors on the paper, spurred the realization that the cell has the capacity to both degrade and synthesize proteins, said Uhlmann. This finding "suddenly opened our eyes that just [protein destruction] can't by itself make [mitotic exit] irreversible." A balance between destruction and synthesis, they speculated, must be at play. Uhlmann and his colleagues tested their hypothesis by interfering with the cell's machinery for cyclin destruction in yeast using inducible promoters. If the cyclins are destroyed, "the cell starts to go out of mitosis," Uhlmann said. But when they inhibited cyclin destruction, cyclin levels recovered, and the cell reverted back to the mitosis phase. This means that even after the proteins have been degraded, the cycle has the capacity to reverse itself via protein synthesis, said Uhlmann, demonstrating that cyclin destruction, though indeed a key driver of mitotic exit, is not what makes mitotic exit unidirectional. If they allowed cyclin destruction to go on longer, however, the cell's mitotic exit did become permanent. That time-lag to irreversibility, Uhlmann said, occurs because cyclin levels regulate a signaling cascade that acts as a series of feedback loops controlling the decision to exit mitosis. The researchers observed increased levels of a protein called Sic1, which inhibits cyclin activity, and suggest that this inhibitor protein is the target of the feedback loop. The cell's cyclin levels thus are not themselves responsible for mitotic exit, but likely provide a signal for the transcription of genes which control the decision to end mitosis, Uhlmann said. Ferrell noted that his group linkurl:published a similar study in 2003;https://www.ncbi.nlm.nih.gov/pubmed/14647386 looking at oocyte maturation in Xenopus. That study identified two opposing factors that controlled the process, and found that weakening the network's positive feedback arm "turned maturation from a completely irreversible process to a reversible one," he wrote. But linkurl:Gary Gorbsky,;https://www.omrf.org/omrf/Research/06/GorbskyG.asp a cell biologist at the University of Oklahoma Health Sciences Center, noted that the cyclin inhibitor protein, Sic1, is not actually an essential protein for mitosis in yeast, so giving it a central role "overstates the situation." Also, he said, the existence of such feedback elements isn't novel: In his view, he said, proteolysis and feedback are both important mechanisms for regulating directionality of the cell cycle, and his group also linkurl:recently identified;https://www.ncbi.nlm.nih.gov/pubmed/19158392 such a feedback system in Xenopus. Uhlmann agreed that Sic1 is not essential to living cells, noting that "We have singled out Sic1 in our experimental setting as an example and to simplify the analysis." He explained that cells do need either Sic1 or a second protein called Cdh1, and that the two are part of distinct but interacting feedback loops. Uhlmann said he believes the kind of feedback system his group has proposed probably drives many types of unidirectional cell decisions -- for example, a stem cell's decision to differentiate. "We've very clearly identified it in budding yeast," he said. "The question is, how does it work in other systems?"
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[March 2009]*linkurl:Cell division rewinds;https://www.the-scientist.com/article/display/23551/
[June 2006]*linkurl:In cell cycle, size matters;https://www.the-scientist.com/article/display/22361/
[25th August 2004]