Telomeres are the protective caps at chromosome ends. In adult cells, telomeres shorten each time a cell divides and this contributes to ageing and cancer. Pluripotent stem cells, however, are specialised cells that exist in the earliest days of development. These pluripotent cells do not age and have the ability to turn into any type of adult cell.
The surprise finding, published today in Nature, shows that telomeres in pluripotent stem cells are protected very differently than telomeres in adult tissues.
“This upends 20 years of thinking on how stem cells protect their DNA,” said Associate Professor Tony Cesare, from the University of Sydney’s Faculty of Medicine and Health, who is Head of the Genome Integrity Unit at Children’s Medical Research Institute (CMRI) and co-leader of a research team that collaborated on this research.
In adult cells, a protein called TRF2 is essential because it arranges DNA at the chromosome end into a “telomere-loop” structure. Removing TRF2 from adult cells causes the chromosomes to become stitched together into one long string, which is incompatible with life.
To the researchers’ astonishment, removing TRF2 from pluripotent stem cells did almost nothing. The chromosomes were normal, the telomere-loops remained, and the cells divided as if nothing happened. Telomeres are therefore protected differently in pluripotent stem cells and adult tissues.
This unexpected finding has major implications for research on ageing, human development, regenerative medicine, and cancer. Previously, researchers expected fundamental mechanisms that protected DNA would be the same in all tissues. This now appears to be incorrect.
This is tremendously exciting for molecular biology and opens up a whole new way of thinking about immortality in stem cells.
“An exciting outcome of this research is that it definitively shows the critical protective element at chromosome ends is the telomere DNA loop,” said Associate Professor Cesare.
“This likely explains why telomere length regulates ageing; cells must need long enough telomeres to make the DNA loops and this becomes difficult as cells age.”
Associate Professor Cesare also highlighted that the discovery was important for understanding stem cells, which are increasingly being used to develop treatments (referred to as regenerative medicine) for many diseases.
“We now realise that the rules for creating telomere loops are entirely different in pluripotent stem cells, suggesting other cellular rules might also be different.
"This is tremendously exciting for molecular biology and opens up a whole new way of thinking about immortality in stem cells, and invites new research into cancer, aging, embryonic and adult development, and regenerative medicine.”
Two independent teams have reported these findings separately – one team was co-led by Associate Professor Cesare at Children’s Medical Research Institute and University of Sydney and by Professor Simon Boulton at the Crick Institute in London, and the other team was led by Dr Eros Lazzerini Denchi at the National Cancer Institute, United States.
Declaration: The authors declare no competing interests.