It was long thought that the key enzyme driving mitosis switched on in the cytoplasm, new evidence shows that's not the case.
Schizosaccharomyces pombe yeast cells. The cell nuclei have been coloured in yellow and the cell membranes in green. Where the cells are dividing, you can see the early stages of mitosis in blue. Credit: The Francis Crick Institute.
Every time a cell divides, it reaches a deciding moment, a tipping point when it chooses to move forward, change state, begin something new and form two new cells.
“At the molecular level, cells are noisy, messy systems, but somehow, they create ordered and reproducible transitions. That’s what I wanted to understand,” says Nitin Kapadia, who led a project exploring one of the most fundamental transitions in biology: the start of a process called mitosis, when a cell commits to dividing into two.
Working in Paul Nurse’s Cell Cycle Laboratory, Nitin, revealed something completely unexpected: the key enzyme driving this process, cyclin dependent kinase (CDK), switches on first in the nucleus, not the cytoplasm as long thought.
“When I started in Paul’s lab, I was new to cell cycle research,” Nitin explains, “So I spent two months reading papers, everything I could find, about how a cell cycles through phases of growth.”
This field of research, steeped in decades of elegant studies, can feel almost complete. “It’s easy to think everything’s already known,” he says. “But when I went back to the original studies, I realised no one had directly shown where the trigger for mitosis starts.”
Drawing on his background in microscopy and biophysics, Nitin built two molecular biosensors that emit a glow when CDK is activated by a molecule called cyclin. This allowed him to track cyclin CDK activity in specific regions of the cell, such as the nucleus or cytoplasm.
The biosensors revealed that CDK activity is switched on in the nucleus, where DNA replicates, before spreading outward through a ‘relay station’ called the centrosome and into the cytoplasm.
This inside out wave pointed to something deeper: the two regions have different thresholds for entering mitosis. In the nucleus, higher cyclin levels are required to activate CDK, and once activated, the system can tolerate levels dipping below threshold without slipping out of mitosis. The cytoplasm, by contrast, operates in a more flexible, sensitive state, requiring lower cyclin levels to make the switch.
“In the nucleus, the distinction between the two states – before and after mitosis – is clear, but in the cytoplasm, it’s more blurred,” Nitin explains. “The stability of this switch means the nucleus doesn’t just initiate mitosis, it also ensures its irreversibility. The nucleus acts as the key pacemaker of the cell cycle, making sure cells only divide when ready. And because CDK is in the nucleus, it is close to the genome so can more easily monitor if it’s fully copied. This helps to protect the genome.”
“One reason I joined Paul’s lab is that he’s into big picture ideas,” adds Nitin. “He’s highly creative and brings in concepts from a range of disciplines like physics and control theory. There’s real value to working in a lab where you can suggest wild ideas to your boss without holding back.”
For Nitin, intellectual freedom is essential for growth as a scientist. It also shaped the paper’s unusual authorship; just two names. In a time when biology papers often list dozens of contributors, Nitin and Paul’s article echoes Paul’s sole-author Nature paper, published 50 years earlier, which was foundational to his 2001 Nobel Prize.
Paul’s mentorship has been indispensable in helping Nitin take his next career step. Now two months into leading his own lab at King’s College London, Nitin is continuing to explore how cells make decisive transitions.
“Independence is the best training an early career scientist can have,” says Paul. “You learn to trust your curiosity. Science moves forward by questioning what is thought obvious and closely following the evidence, even when it leads to surprising results."
