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Mutation frequency dynamics in HPRT locus in culture adapted hESCs and iPSCs correspond to their differentiated counterparts

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KRUTÁ Miriama ŠENEKLOVÁ Monika RAŠKA Jan SALYKIN Anton ZERZÁNKOVÁ Lenka PEŠL Martin BÁRTOVÁ Eva FRANEK Michal BAUMEISTEROVÁ Aneta KOŠKOVÁ Stanislava NEELSEN Kai J. HAMPL Aleš DVOŘÁK Petr ROTREKL Vladimír

Druh Článek v odborném periodiku
Časopis / Zdroj Stem Cells and Development
Fakulta / Pracoviště MU

Lékařská fakulta Rektorát

Citace
Doi http://dx.doi.org/10.1089/scd.2013.0611
Obor Genetika a molekulární biologie
Klíčová slova mutation frequency; human embryonic stem cells; induced pluripotent stem cells; hypoxanthine phosphoribosyltransferase; base excision repair; apurinic/apyrimidinic endonuclease
Popis The genomic destabilization associated with the adaptation of human embryonic stem cells (hESCs) to culture conditions or the reprogramming of induced pluripotent stem cells (iPSCs) increases the risk of tumorigenesis upon the clinical use of these cells and decreases their value as a model for cell biology studies. Base excision repair (BER), a major genomic integrity maintenance mechanism, has been shown to fail during hESC adaptation. Here, we show that the increase in the mutation frequency (MF) caused by the inhibition of BER was similar to that caused by the hESC adaptation process. The increase in MF reflected the failure of DNA maintenance mechanisms and the subsequent increase in MF rather than being due solely to the accumulation of mutants over a prolonged period, as was previously suggested. The increase in the ionizing radiation-induced MF in adapted hESCs exceeded the induced MF in non-adapted hESCs and differentiated cells. Unlike hESCs, the overall DNA maintenance in iPSCs, which was reflected by the MF, was similar to that in differentiated cells regardless of the time spent in culture and despite the upregulation of several genes responsible for genome maintenance during the reprogramming process. Taken together, our results suggest that the changes in BER activity during the long-term cultivation of hESCs increase the mutagenic burden, whereas neither reprogramming nor long-term propagation in culture changes the MF in iPSCs.
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