. 2014 Feb 6;5(2):e1045. doi: 10.1038/cddis.2013.477

Table 2. Possible pathways to DSB formation and cell death in pemetrexed-treated cells.

Possible route to cell death	Problem with hypothesis
UNG^+/+ cells
Stalled replication due to nucleotide pool aberrations caused by reduced dTTP	Does not explain differential sensitivity in UNG^+/+ and UNG^−/− cells.
Endonuclease cleavage of uracil and/or AP sites	No endonucleases with uracil activity have been studied in pemetrexed treated cells. Products of APE incision are rapidly targeted by activities of Polβ and downstream BER.
Futile cycles of BER	UNG^+/+ cells are more resistant than UNG^−/− cells, suggesting excision of uracil protects from pemetrexed cytotoxicity.

UNG^−/− cells
Uracil-mediated replication fork stall and collapse	Currently there is no available method to directly interrogate various degrees of uracil base substitution within living cells.
Uracil-mediated endonuclease cleavage	No endonucleases with uracil activity have been studied in this context.