Removal of oxidatively generated DNA damage by overlapping repair pathways

Abstract

It is generally believed that the mammalian nucleotide excision repair pathway removes DNA helix-distorting bulky DNA lesions, while small non-bulky lesions are repaired by base excision repair (BER). However, recent work demonstrates that the oxidativly generated guanine oxidation products, spiroimininodihydantoin (Sp), 5-guanidinohydantoin (Gh), and certain intrastrand cross-linked lesions, are good substrates of NER and BER pathways that compete with one another in human cell extracts. The oxidation of guanine by peroxynitrite is known to generate 5-guanidino-4-nitroimidazole (NIm) which is structurally similar to Gh, except that the 4-nitro group in NIm is replaced by a keto group in Gh. However, unlike Gh, NIm is an excellent substrate of BER, but not of NER. These and other related results are reviewed and discussed in this article.

Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine

“…The BER pathway mitigates the mutagenic and toxic properties of a wide array of DNA nucleobase modifications [12, 50]. The key players of this pathway are a cadre of DNA glycosylases that scour the genome and initiate the repair of specific types of base modifications in DNA by hydrolyzing the N-glycosidic bond between the damaged base and the 2’-deoxyribose sugar, affording apurinic/apyrimidinic (AP) sites within DNA [4].…”

Cooperation and interplay between base and nucleotide excision repair pathways: From DNA lesions to proteins

“…While both BER and NER pathways have been conventionally associated with specific substrates, growing evidence shows a significant cooperation between these two repair mechanisms, and has recently been reviewed (Melis et al, 2013;Limpose et al, 2017;Shafirovich and Geacintov, 2017). The relevance of this potential interaction includes the fact that NER deficient (XP and CS) patients may develop developmental and neurological symptoms, related to premature aging, that can be due to endogenous lesions, such as DNA damage induced by oxidation, which are normally considered substrates for BER.…”

Synthesis of Oligonucleotides Containing the N6‐(2‐Deoxy‐α,β‐d‐erythropentofuranosyl)‐2,6‐diamino‐4‐hydroxy‐5‐formamidopyrimidine (Fapy⋅dG) Oxidative Damage Product Derived from 2′‐Deoxyguanosine

“…In addition, recent evidence suggests that damaged nucleotides may also play a role in regulating transcription . As the most readily oxidized native nucleotide, 2′‐deoxyguanosine modifications have been of significant interest . Of these, 7,8‐dihydro‐8‐oxo‐2′‐deoxyguanosine (8‐OxodGuo), the two‐electron oxidation product resulting from formal hydroxyl radical addition to the C8‐position of dG (C8 Add , Scheme ) is the most well studied lesion .…”

“…Inferential support for the biological significance of Fapy⋅dG is that not only is it recognized by the proteins involved in repairing guanine oxidation (GO) products, but it is repaired in a manner to guard against introducing mutations . For instance, the bacterial (Fpg) and human glycosylases (hOGG1) that selectively recognize 8‐OxodGuo opposite dC versus dA act similarly on Fapy ⋅ dG.…”