Repair of Uracil Residues
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Repair of Uracil Residues

The integrity and accuracy of the DNA is of critical importance to the cell, but the organization of DNA into chromatin in eukaryotic cells afford little protection against formation of DNA base damage generated spontaneously through hydrolysis, since DNA remains hydrated in chromatin. Two frequently occurring hydrolytic reactions are depurination to produce non-coding abasic sites, and deamination of cytosine (C) to uracil (U) (Ref.1). Deamination of cytosine to uracil is one of the major pro-mutagenic events in DNA, causing G: C->A: T transition mutations if not repaired before replication. Uracil can also occur in DNA through misincorporation of dUMP (Deoxyuridine Monophosphate) opposite adenine (A) residues during replication to generate U: A base pairs, the rate of misincorporation being proportional to the size of the dUTP (Deoxyuridine Triphosphate Nucleotidohydrolase) pool because dUTP is present in the cell as a precursor for the biosynthesis of dTTP (Ref.2).

Uracil residues in DNA, which arise spontaneously from cytosine through deamination are removed rapidly by BER (Base Excision Repair), initiated by one of the two major UDGs (Uracil-DNA Glycosylases) activities in mammalian cells, UNG2 (Uracil-DNA Glycosylase-2) and SMUG1 (single-strand Selective Monofunctional Uracil DNA Glycosylase-1). UNG2 primarily removes uracil misincorporated during replication (Ref.3). Both UNG2 and SMUG1 are able to remove uracil from U: A as well as U: G base pairs, and the resulting Apurinic or Apyrimidinic (AP) sites are repaired by the short-patch BER pathway. APE1 (AP-Endonuclease-1) incises the damaged strand 5 to the AP-site generating a 3-hydroxyl terminus and a 5- dRP (deoxyribose phosphate) moiety. This cuts the DNA backbone, leaving a single strand nick. DNA Pol-I (Polymerase-I) interacts with this nick, using its 5->3 Exonuclease activity and its 5->3 Polymerase activity to "translate" the nick. Degrading and synthesizing at the same time accomplish this activity. The repair process takes one of two routes. The resulting single-nucleotide gap is filled in by Pol-Beta, which incorporates the dRP moiety (dCMP-nucleotide carrier of cytosine), removes the sugar-phosphate flap and DNA Ligase seals the resulting nick. The alternative route occurs when PolBeta errs, and dTMP, the carrier of thymine, has been erroneously inserted into the gap. It is recognized and removed by the 3->5 proofreader, APE1. Pol-Beta then correctly fills the gap by incorporating a dCMP residue, after which ligation by DNA Ligase-III restores the DNA to its original state. XRCC1 also participates in this pathway as a scaffold protein interacting with Pol-Beta and Ligase-III (Ref.4).

UGDs are very conservative enzymes and have an important function in DNA replication. dUTPase plays a pivotal role in regulating cellular dUTP pools, and accumulation of this enzyme during TS (Thymidylate Synthesis) inhibition results in repeated cycles of uracil misincorporation and detrimental repair leading to strand breaks and cell death (Ref.5).