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Review
. 2013 Apr 1;5(4):a012583.
doi: 10.1101/cshperspect.a012583.

Base Excision Repair

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Free PMC article
Review

Base Excision Repair

Hans E Krokan et al. Cold Spring Harb Perspect Biol. .
Free PMC article

Abstract

Base excision repair (BER) corrects DNA damage from oxidation, deamination and alkylation. Such base lesions cause little distortion to the DNA helix structure. BER is initiated by a DNA glycosylase that recognizes and removes the damaged base, leaving an abasic site that is further processed by short-patch repair or long-patch repair that largely uses different proteins to complete BER. At least 11 distinct mammalian DNA glycosylases are known, each recognizing a few related lesions, frequently with some overlap in specificities. Impressively, the damaged bases are rapidly identified in a vast excess of normal bases, without a supply of energy. BER protects against cancer, aging, and neurodegeneration and takes place both in nuclei and mitochondria. More recently, an important role of uracil-DNA glycosylase UNG2 in adaptive immunity was revealed. Furthermore, other DNA glycosylases may have important roles in epigenetics, thus expanding the repertoire of BER proteins.

Figures

Figure 1.
Figure 1.
Chemistry of common base lesions and abasic sites.
Figure 2.
Figure 2.
Subpathways in base excision repair (BER). BER takes place by short-patch repair or long-patch repair that largely use different proteins downstream of the base excision. The repair process takes place in five core steps: (1) excision of the base, (2) incision, (3) end processing, and (4) repair synthesis, including gap filling and ligation.
Figure 3.
Figure 3.
Structural basis for interaction of BER enzymes with their DNA substrates. Overall structure (upper panel) and close-up of active site (lower panel) of three different repair proteins in complex with their DNA substrates. Recognition and extrahelical flipping of damaged base (8-oxoG) by DNA glycosylase (OGG1) (Radom et al. 2007), PDB code 2NOZ; binding of AP-site by AP-endonuclease (APE1) (Mol et al. 2000), PDB code 1DE8; and recognition of 5′ flap by structure specific endonuclease (FEN1) (Tsutakawa et al. 2011), PDB code 3Q8K. The chemical structures of DNA substrates are shown in the middle panel.
Figure 4.
Figure 4.
Repair of 8-oxoG (*G) resulting from incorporation of 8-oxo-dGTP (d*GTP) in the dNTP pool (left) and from oxidation of G in DNA (right) require different mechanisms. Most of the 8-oxo-dGTPs in the dNTP pool are hydrolysed by MTH, thus avoiding misincorporation during DNA replication. If 8-oxo-dGTP is misincorporated opposite an A in the template strand and the A is removed by MYH, this repair process would result in a mutation. Alternatively, repair by MMR may restore the correct basepair. Repair of 8-oxoG in DNA (right panel): BER initiated by OGG1 removes the majority of 8-oxoG oxidized in DNA. If 8-oxoG is not repaired before DNA replication, replicative DNA polymerases δ and ε incorporate dAMP opposite 8-oxoG with a high frequency. The resulting 8-oxoG:A is repaired by MYH, restoring the correct basepair. However, if the 8-oxoG:A basepair is not repaired before a second round of DNA replication, it leads to an A:T transversion mutation.

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