Original article from STEM CELLS
“Deficient DNA Damage Response and Cell Cycle Checkpoints Lead to Accumulation of Point Mutations in hESCs”
The long term culture of human embryonic stem cells (hESCs) is known to have some detrimental effects, such as the acquirement of an abnormal karyotype, increased copy number variations, loss of heterozygosity, increased rate of proliferation and resistance to apoptosis (Draper et al, Baker et al and Narva et al). These changes are all indicative of the gain of a tumourigenetic phenotype, so it is not surprising that culture-adapted hESCs form teratocarcinomas when transferred into severe combined immunodeficiency (SCID) mice, while non-adapted hESCs lead to teratoma formation (Solter, Blum and Benvinisty and Andrews). How long term culture leads to this effect is relatively unknown, although it is thought that uncontrolled cell cycle checkpoints and abnormal DNA damage response and repair are among the mechanisms contributing to hESC adaptation and major karyotypic changes (Rodriguez-Jiminez et al, Mantel et al and Momcilovic et al). In a study described in Stem Cells, researchers from the laboratories of Peter W. Andrews and Thierry Nouspikel at the University of Sheffield, United Kingdom have now analyzed one mode of DNA damage repair; Nucleotide Excision Repair (NER) with respect to the DNA damage response and cell cycle checkpoints in hESCs and have found that point mutations result from a combination of defects in the DNA damage signaling pathway which leads to incomplete arrest at cell cycle checkpoints, the rapid proliferation rate of hESCs and insufficient NER activity (Hyka-Nouspikel et al).