Research Highlights | Published:

DNA repair: Chemo's modus operandi

Nature volume 459, page 12 (07 May 2009) | Download Citation


The chemotherapeutic 5-fluorouracil has been a first-line treatment for diseases such as colorectal cancer for decades, even though it's not clear exactly how the drug works.

In cells, 5-fluorouracil is converted into several metabolites that mimic the natural RNA base uracil. The metabolites inundate the cell, some becoming incorporated into RNA and even DNA in dividing cells. Uracil in DNA activates a family of DNA-repair proteins devoted to removing it, but the unnatural 5-fluorouracil triggers incomplete repair, causing an accumulation of strand breaks in the DNA and eventual cell death. Primo Schär of the University of Basel in Switzerland and his colleagues examined mouse and human cells responding to the drug and identified thymidine DNA glycosylase (TDG) as the uracil-removing protein responsible for the breaks. Without TDG activity, cancer cells become more resistant to the drug.

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