Genetic instability in human embryonic stem cells: prospects and caveats

Human embryonic stem cells (hESCs) display a leaky G1/S checkpoint and inefficient nucleotide excision repair activity. Maintenance of genomic stability in these cells mostly relies on the elimination of damaged cells by high rates of apoptosis. However, a subpopulation survives and proliferates actively, bypassing DNA damage by translesion synthesis, a known mutagenic process. Indeed, high levels of damage-induced mutations were observed in hESCs, similar to those in repair-deficient cells. The surviving cells also become more resistant to further damage, leading to a progressive enrichment of cultures in mutant cells. In long-term cultures, hESCs display features characteristic of neoplastic progression, including chromosomal anomalies often similar to those observed in embryo carcinoma. The implication of these facts for stem cell-based therapy and cancer research are discussed.