Base Excision Repair

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.

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

“…Evidence from several laboratories indicates that BER intermediates are often Aag has been shown to act on Uracil (an Ung substrate) and 8-oxoG (substrates for both Ogg1 and Neil1) (9,10,42). Thus, in contrast to most other DNA glycosylases that have a narrow substrate range, Aag catalyzes the excision of a broad range of modified bases; this is achieved by its unique active site structure that can both discriminate against normal DNA bases and yet accommodate a structurally diverse set of aberrant DNA bases (8,9).…”

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

“…The removal of TMZ‐induced methylated DNA bases by the base excision repair (BER) pathway generates apurinic/apyrimidinic (AP) single‐stranded (ss) DNA sites which are fragile and can progress into dsDNA breaks (Krokan and Bjoras, 2013). We reasoned that a DNA protective role of CTRP8 may involve a reduction in the number of detectable AP sites in genomic DNA.…”

“…3C). Exposure to CTRP8 caused an exclusive increase in protein production of the monospecific DNA glycosylase N‐methylpurine DNA glycosylase (MPG), a key BER‐initiating enzyme which removes altered DNA bases and generates AP sites (Kim and Wilson, 2012; Krokan and Bjoras, 2013), whereas other BER members, including APE1, XRCC1, or DNA polymerase B (DNA pol β), remained unchanged as determined by quantitative western blot analysis in patient GBM‐1/2 (Fig. 3B, D, F; Fig.…”

“…The methylation at the N 7 position of guanine (N 7 ‐MeG; 80–85%) and the N 3 position of adenine (N 3 ‐MeA; 8–18%) constitute the majority of TMZ‐induced DNA methylations repaired by the base excision repair (BER) pathway. BER is the predominant DNA repair system in mammalian cells and repairs small cytotoxic DNA base lesions resulting from oxidized, alkylated, or deaminated nucleotides (Kim and Wilson, 2012; Krokan and Bjoras, 2013). The remaining 5–10% of TMZ‐induced DNA‐methylated lesions occur as O 6 ‐MeG which is the substrate for the enzyme O 6 ‐methylguanine‐DNA methyltransferase (MGMT) (Sarkaria et al ., 2008).…”

“…This generates a cytotoxic 5′‐deoxyribosyl phosphate (dRP) residue which is commonly removed by the dRP lyase activity of DNA polymerase β (Sobol et al ., 2000). DNA polymerase β adds the complementary base and the X‐ray repair cross‐complementing group 1 (XRCC1)/DNA ligase III complex performs the phosphodiester bond formation to complete BER (Krokan and Bjoras, 2013). Inhibition of BER in MPG overexpressing human glioma sensitizes these cells to TMZ in vitro and in vivo , but this cytotoxic effect is diminished at higher cellular levels of the rate‐limiting BER enzyme DNA polymerase β (Kim and Wilson, 2012; Tang et al ., 2011).…”