Mystery solved as protein expressed in response to telomere shortening identified.
Telomeres are critical for maintaining genomic integrity with telomere dysfunction or shortening commonly acquired during the process of tumour development. To add to this cancer cells require a mechanism to elongate their telomeric DNA in order to continue dividing indefinitely. A mechanism for telomere elongation is one of the key steps in cellular immortalization.
Zscan4 is a DNA-binding protein that functions for telomere elongation and genomic stability. It has posed a mystery during the past decade as it is specifically expressed in two-cell stage embryos during mouse development and transiently expressed in a minor population of embryonic stem cells (ESCs). It is unclear why the protein is expressed in these specific situations. Now, a study from researchers at RIKEN shows that Zscan4 is actually a repair mechanism triggered by the shortening of telomeres that takes place during cell division. The team state that their findings suggest that Zscan4 is activated to recover shortened telomeres during extended cell cycles, irrespective of the pluripotent status. The opensource study is published in the journal Stem Cell Reports.
Previous studies show that Zscan4 functions for telomere elongation and genomic stability and is considered a rejuvenation factor. Since activation of Zscan4 is involved in telomere elongation, the group speculate that the extended cell cycles accompanied by Zscan4 activation reflect the time for telomere recovery. The current study shows that Zscan4 is activated when the cell-cycle lengths become long, irrespective of the pluripotent status, presumably sensing shortened telomeres.
The current study utilised mouse embryonic stem cells, where snapshots of the cells were taken at 60-minute intervals to investigate the transient expression of Zscan4. Results show that the expression of Zscan4 is linked to the length of the stem cell cycles, which have different cell cycle lengths. Data findings show that Zscan4 tends to be expressed in cells with longer cell cycles.
Results show that once the cells had expressed Zscan4, in the next generation they had shorter cell cycles, verifying the hypothesis that cells slow their cycle in order to allow the recovery of telomeres, and then speed it up again when the repair is completed. Data findings show that the cells with longer cell cycles did in fact have shorter telomeres.
In a final test, the lab engineered stem cells that had a deficiency in Zscan4 expression and, in agreement with the hypothesis, those cells failed to recover from the longer cell cycles exhibiting a higher likelihood of undergoing cell death.
The team surmise that their findings have helped them to gain a new understanding of the function of Zscan4 and how pluripotent cells work to maintain their ability to replicate in the face of telomere shortening. For the future, the researchers state that their work could help to ensure the safety of iPS cells, which are currently moving into clinical use.