Mutation spectrum in the lacI gene, induced by γ-radiation in aqueous solution under oxic conditions

Wijker, Carola A; Wientjes, Natasja M.; Vincent, Maxence S.; Lafleur, M.V.M.

doi:10.1016/s0027-5107(98)00072-4

Cited by 10 publications

(2 citation statements)

References 27 publications

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“…The second mechanism is oxidative damage‐induced telomerase‐mediated shortening [23]. This model is also supported by finding, that IR‐induced mostly oxidative DNA damage [25] to telomeres appears to cause more genome instability in human fibroblasts expressing human telomerase reverse transcriptase (hTERT) than does damage induced by Cr(VI) [24], processing of which is dependent on MSH2‐MSH3 [26]. The increase in the DSB burden after time (not limited to the telomeres) in late passage hESC in our comet analysis (Fig.…”

Section: Discussionmentioning

confidence: 79%

“…Under normal conditions, normal tissues can accumulate up to 500,000 apurinic sites per cell per day [22], and a significant number of these apurinic lesions may derive from clustered oxidative damage [recently reviewed in [23–29, 30]]. hESCs appear to be very proficient in the repair of certain types of DNA damage [7], especially DNA damage after exposure to IR [31].…”

Section: Discussionmentioning

confidence: 99%

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Decrease in Abundance of Apurinic/Apyrimidinic Endonuclease Causes Failure of Base Excision Repair in Culture-Adapted Human Embryonic Stem Cells

et al. 2013

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The inevitable accumulation of chromosomal abnormalities in human embryonic stem cells (hESCs) during in vitro expansion represents a considerable obstacle for cell replacement therapies. To determine the source of chromosomal abnormalities, we examined hESCs maintained in culture for over 55 months for defects in telomere maintenance and DNA repair. Although prolonged culture affected neither telomerase activity nor nonhomologous end joining, the efficiency of base excision repair (BER) was significantly decreased and correlated with reduced expression of apurinic/apyrimidinic endonuclease 1 (APE1), the major nuclease required for BER. Interestingly, the expression of other BER enzymes was unchanged. Addition of human recombinant APE1 protein to nuclear extracts from late passage hESCs increased BER efficiency to the level typical of early passage hESCs. The link between BER and double-strand breaks (DSB) was demonstrated by decreased DSB release after downregulation of APE1 in early passage hESCs via siRNA. Correspondingly lower APE1 level in late passage hESC resulted in slower and less intensive but long lasting DSB release upon ionizing radiation (IR). Downregulation of APE1 in early passage hESCs also led to approximately 30% decrease in c-H2AX signaling following IR, similar to that in late passage hESCs. We suggest that downregulation of APE1 significantly contributes to the failure of BER during long-term culture of hESCs, and further that BER failure is one of the factors affecting the genomic instability of hESCs by altering BER-dependent DSB release and cell cycle/checkpoint signaling. STEM CELLS 2013;31:693-702 Disclosure of potential conflicts of interest is found at the end of this article.

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