An ageing question: do embryonic stem cells protect their genomes?

Many physiological and cellular processes contribute to the ageing of individuals. One hypothesis argues that the genomes of somatic cells accumulate mutations, which, in turn, alter the metabolism of the cells and contribute to the ageing process. The frequency of somatic mutation approaches 10(-4) and the majority of mutagenic events at heterozygous loci is due to loss of heterozygosity as a consequence of mitotic recombination. A corollary to the argument that somatic cells accumulate mutations is that cells of the germ line and ES cells have a greater requirement for maintaining the integrity of their genomes. In the former case, a high somatic mutation frequency predicts an increase in somatic disease, which limits our lifespan. The corollary is that cells of the germline and ES cells must minimize the mutational burden to limit the frequency of congenital disease and to ensure the proper transmission of undamaged DNA to the gene pool. This report describes two mechanisms utilized by murine ES cells to minimize DNA damage within the proliferative pool. In the first case, murine ES cells display a frequency of mutation and mitotic recombination that is about 100-fold lower than that observed in somatic cells. Second, ES cells lack a G1 checkpoint following DNA damage. When subjected to ionizing radiation, the fraction of apoptotic cells increases to about 40%. Ectopic expression of Chk2 is sufficient to establish a G1 arrest and the concomitant protection from cell death.