Folate and Colorectal Cancer in Rodents: A Model of DNA Repair Deficiency

Figure 1

Biochemistry of base excision repair in uracil removal. Uracil removal is carried out as depicted, with initiation of removal by a uracil-excising DNA glycosylase (UDG depicted). All the uracil-excising glycosylases are monofunctional and leave behind an abasic lesion with an intact DNA backbone. An endonuclease (Apex 1) incises the DNA backbone 5′ to the abasic lesion, generating a 3′hydroxyl group and a 5′deoxyribose flap. A DNA polymerase (DNA polymerase β) inserts the correct nucleotide, then, in conjunction with a scaffolding protein (XRCCI), excises the deoxyribose flap. This step represents the rate-determining step in uracil-initiated base excision repair. Ligation of the scission in the phosphodiester backbone (ligase III and Xrcc1) completes repair and restores intact DNA structure. The single-strand break induced by Apex1 persists until ligation is complete and presents a potentially cytotoxic lesion if left incompletely repaired.