DNA damage necessary for cell development
Canadian scientists have discovered that stem cells intentionally damage their own DNA in order to regulate development. The breakthrough findings clear up the mystery of how cell death proteins actually promote cell differentiation and cell development.
The study, led by Dr. Lynn A. Megeney of the Ottawa Hospital Research Institute, published in the Proceedings of the National Academy of Science found that two cell-death proteins, caspase 3 and caspase activated DNase (CAD), previously thought of as damaging were actually performing a necessary maintenance function: namely, triggering cellular development.
This may well change the focus of some current research which has sought to inhibit these death proteins in order to prevent cell damage. The hypothesis was that these cell-death proteins’ main function was to kill the cell, however, Megeney’s findings suggest that DNA damage is the penultimate step to cell differentiation, not necessarily to cell death.
Megeney had always been puzzled by the presence of supposed cell-death proteins in single-celled organisms, such as yeast. “Why would a single-celled organism, which exists only to replicate, have a pathway whose sole purpose was to kill it? It makes perfect sense for a multi-cellular organism because there are things we want to get rid of but it defies logic in a single cell life form. To me, that suggested there were other functions going on.”
Numerous studies in recent years have shown that inhibiting caspase 3 also inhibits the development of the cell. What Megeney and his team found in this most recent study is that the DNA damage which is triggered by caspase 3 and CAD is critical to the development of the adult cell. The stem cells will intentionally cut and repair the DNA in order to activate genes that promote the development of new tissue. Megeney explains, “If you think about a stem cell versus an adult cell, a lot of things happen in the progression. You have to turn hundreds of genes on and hundreds of genes off in a very short timeframe to get adult cells. Controlled DNA damage is actually a great way to manage this process.”
One question that arises from these findings is what happens when a cell’s DNA does not repair properly? Would it lead to a mutation of the cell and if so, could that mutation be passed on to the cell’s descendants?
In response to these questions, Megeney’s current research seeks to map the DNA breaks that occur during the cell maturation process. “If we can map the breaks and determine how a cell uses these DNA breaks to spur development, then perhaps we can use this knowledge to push cell development in specific ways that could be useful for treating illness or disease.”
Photo: Red staining indicates areas of DNA damage in healthy muscle stem/progenitor cells under going differentiation.