Unveiling a Reversible Pre-Commitment Stage in Cell Division

Researchers at Weill Cornell Medicine have uncovered a surprising new step in cell division. Before diving headfirst into replication, cells may spend hours or even a day in a "wait and see" state.

This reversible pause allows them to assess conditions and ensure it is the right time to copy their DNA. This fundamental discovery, published in Nature, sheds light on a previously unknown aspect of cell biology. Understanding the dynamics of this pre-commitment stage could pave the way for novel therapies targeting cancer and other diseases linked to cell division.

The scientists created new instruments that let them monitor the activation state of E2F, a transcription factor protein that has long been regarded as the master switch that triggers cell division in mammals over time. The surprising discovery they made was that E2F can remain in a potentially long-lasting state of partial and reversible activation before fully committing to cell division, or it can return to its typical, non-dividing, "quiescent" state.

Pre-commitment state of cell division appears to be a safety mechanism to prevent inappropriate cell division and may also activate DNA-repair functions, though its exact role in cell division is still unknown. Regardless, it seems to be a fundamental—and as of yet unidentified—aspect of cell biology, with possible implications for the knowledge of cancer, wound healing, and other processes involving cell division.

We suspect, for example, that some types of cancer cell linger in this intermediate, pre-division state to improve their chances of survival.”

Dr. Tobias Meyer, Joseph Hinsey Professor, Cell & Developmental Biology, Weill Cornell Medicine

Dr. Tobias Meyer is also a Professor of biochemistry.

Dr. Yumi Konagaya, a Postdoctoral Researcher in the Meyer Laboratory during the study and currently a principal investigator at Riken, a national research institute in Japan, is the study's first author and co-corresponding author with Dr. Meyer.

The fundamental process of cell division, which is required for wound healing and general tissue maintenance even in adult organisms, is what drives the growth and development of living things. Although it is known that different input signals cause E2F to become activated, the mechanism underlying this activation has long been a mystery. Since input signals can fluctuate greatly and the activation process is theoretically highly sensitive to them, how does the cell prevent unwarranted, continuous E2F activations and cell divisions?

Dr. Konagaya created the first collection of techniques to monitor the precise activation status of E2F and its signaling partners in individual cells as they transition from the quiescent state to the process of division to answer this question. Using these new resources, she noticed that E2F, which is partially activated by a series of chemical changes known as phosphorylations, frequently stays in an extended, partial-activation, or "primed" state where some but not all of the required phosphorylations have taken place.

It became clear that cells can stall in this primed state for more than a day before returning to quiescence or advancing to cell division.”

Dr. Yumi Konagaya, Principal Investigator, Riken

According to the researchers, this intermediate primed state likely allows cells to sense and integrate the fluctuating signals associated with cell division, thereby smoothing out "noise" and reducing the risk of inappropriate division. They also suspect that this state has additional functions, such as facilitating DNA repair, since cells in this state exhibit signs of activated DNA-repair processes. Dr. Meyer noted that a DNA-repair function could benefit both cancer cells and healthy cells.

Cancer cells often die when they divide because of the DNA damage they have accumulated, but this intermediate state induces DNA damage-repair machinery, so maybe some cancers use this state to repair themselves before dividing.”

Dr. Tobias Meyer, Joseph Hinsey Professor, Cell & Developmental Biology, Weill Cornell Medicine

The researchers plan to investigate the function of intermediate pre-division states in cancers. Theoretically, if they understood the distinctive phosphorylation pattern of the cancers, they could create tests to detect them in this intermediate state and improve treatment options.