The Persistence of Memory

 

Authors: Katarzyna M. Kedziora & Jeremy E. Purvis

DOI: 10.1038/nature23549

By: Ehsan Moaseri, Behzad Changalvaie

 

A main principle of cell theory is that cells arise from pre-existing cells. This means that every daughter cell will inherit its mother’s genome, and will pass it on to two daughters when it divides. Along with the genome, daughter cells can inherit a number of biochemical characteristics from the mother cells. An example characteristic is that cells may or may not reproduce; some cells may proliferate (e.g. divide and create additional cells), while others may enter a resting state known as quiescence (where they do not produce additional cells). But how do cells “decide” whether they proliferate or enter quiescence? Recent trials on cells’ reproductive behavior may answer this question.

To study the cells’ behavior, researchers exposed mother cells to different growth signals and/or DNA damage. The daughter cells, in which the mother cell had been exposed to growth signals, had a high level of the protein cyclin D1. On the other hand, cells exposed to DNA damage had high levels of the protein p21. It should be noted that cyclin D1 promotes proliferation and p21 is a potent preventer of proliferation. These results indicate that the daughter cells “remember” their mother cells’ history of exposure to growth signals and/or DNA damage. In fact, the balance between cyclin D1 and p21 proved to be a reliable predictor of whether cells would undergo proliferation or enter quiescence.

Although the balance between cyclin D1 and p21 predicts proliferation behavior, it is highly unlikely that inheritance of these factors is the basis of cellular memory. P21 and cyclin D1 have very short lifetimes, and it is highly unlikely that they would be present in the phase where the daughter cells attempt proliferation. Therefore, researchers have concluded that the cells have a more persistent form of memory. They found out that the responding messenger RNA molecule and the activator of cyclin D1 and p21 last roughly ten times longer than their protein counterparts.  The figure above shows how the balance between cyclin D1’s mRNA and p21’s activator (p53) can affect the fate of daughter cells.

These experiments showed that the levels of only two molecules can drastically affect a single cell’s behavior with exceptional accuracy. The proliferation-quiescence decisions have an ultrasensitive response to changes in the ratio of D1 and p21. This result opens up the possibility that other cell-fate choices, such as a cell’s decision to self-renew or differentiate, is determined by a small set of memory signals. This concept of competing molecular memories is an attractive research topic that raises many questions. For example, why do some pairs of daughter cells make different reproductive decisions from one another? Is this difference caused by different distribution of D1 and p21 in each cell? Another question is how molecular memories cooperate with external signals? For example, there is a chance of additional DNA damage during a cell’s growth phase, signals from neighboring cells, and mechanical forces. How would these forces affect the biochemical characteristics of the resulting cells? Many of these questions remain to be answered and are topics of interest to researchers.

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