Scientists from the University of North Carolina (UNC), USA, have discovered a specific cluster that helps unwind DNA strands during cell division and plays a key role in stem cells in the immature state. The results of the study are published in the journal eLife.
The work of American scientists sheds light on the biology of stem cells and offers new molecular approaches for their control. Stem cells have regenerative properties that can revolutionize medicine, but to realize this potential, there is not enough knowledge about the work of these cells. The study also provides a better understanding of how cancer cells manage to sustain rapid cell division and prevent their death.
“Studies like this help explain the underlying biology of rapidly dividing cells and may inform the development of future therapies, for example stem cell therapies or cancer treatments”, – said study senior author Jean Cook.
The study focused on a protein cluster, called the minichromosome maintenance complex (MCM), which is known to be the main factor associated in cell division.
The process of cell division begins, in part, by loading MCM complexes onto its chromosomes. This is necessary for properly unwind chromosomal DNA during cell division, resulting in the formation of two new sets of chromosomes – one for each daughter cell.
“If MCM loading isn’t completed successfully prior to cell division, there’ll be a risk of major DNA mutations and death for the resulting daughter cells”, – said study first author Jacob Matson, a PhD candidate in the Cook laboratory
Despite the importance of MCM loading, cell types vary greatly in the time they have to prepare for cell division. For example, stem cells go through this preparatory phase, known as the G1 phase of the cell cycle, in a short time, unlike mature differentiated cells, such as skin cells or cardiomyocytes. How stem cells manage to pass G1 phase so rapidly, avoiding the risks of incomplete MCM loading and resultant DNA damage, has been a mystery.
One of the theories is that stem cells somehow maintain a higher rate of MCM loading so that they can accomplish the necessary loading within their shorter G1 gaps. To study this process, researchers used a highly sensitive assay, which they developed to measure the speed of MCM loading.
They found that stem cells do indeed load MCM complexes much faster than mature, already differentiated cells. In addition, the chemical stimulation of the transformation of stem cells into more mature types markedly slowed the maturing cells’ MCM loading rates..
The coupling of MCM loading and cellular differentiation worked in the opposite direction too.
Inducing slower MCM loading in stem cells caused them to differentiate more quickly”, – Matson said.
The results show that the attachment rate of MCM is an important factor in the development of cells. It is the speed of this process that affects the maintenance of the immature state of stem cells.
In addition, the results of the study suggest that stimulation of MCM loading rate to more mature cells can help return them to the stem cell state. “Reprogramming” of normal cells into induced pluripotent stem cells is carried out in laboratories around the world and is seen as a potential source of stem cells for treatment in the future.
However, the standard methods used for such reprogramming are not as effective as researchers would like.
“Conceivably, artificially speeding up MCM loading would make this reprogramming process more efficient”, – Cook said.
Currently, Cook and her colleagues are trying to better understand the biological mechanisms by which cells move their MCM loading rates up or down.
The UNC researchers are now studying the role of MCM loading rates in oncological diseases. For example, some cancer cells are very disposed to DNA errors when dividing. Cook and her colleagues suspect that in some cases this “genomic instability” arises from cells’ failure to improvement their MCM loading speed as their cell division accelerates.