Uracil DNA glycosylase (UNG) loss enhances DNA double strand break formation in human cancer cells exposed to pemetrexed.

ABSTRACT: Misincorporation of genomic uracil and formation of DNA double strand breaks (DSBs) are known consequences of exposure to TS inhibitors such as pemetrexed. Uracil DNA glycosylase (UNG) catalyzes the excision of uracil from DNA and initiates DNA base excision repair (BER). To better define the relationship between UNG activity and pemetrexed anticancer activity, we have investigated DNA damage, DSB formation, DSB repair capacity, and replication fork stability in UNG(+/+) and UNG(-/-) cells. We report that despite identical growth rates and DSB repair capacities, UNG(-/-) cells accumulated significantly greater uracil and DSBs compared with UNG(+/+) cells when exposed to pemetrexed. ChIP-seq analysis of γ-H2AX enrichment confirmed fewer DSBs in UNG(+/+) cells. Furthermore, DSBs in UNG(+/+)

SUBMITTER: Weeks LD 

PROVIDER: S-EPMC3944228 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature