Salvage of oxidized guanine derivatives in the (2′-deoxy)ribonucleotide pool as source of mutations in DNA

Abstract

Recent evidence suggests that salvage of 8-oxodG and 8-oxoGua can contribute substantially to levels of 8-oxoGua in DNA and RNA. However, it remains to be determined if this mechanism contributes to mutagenesis and disease. This review covers the predominant methods for detecting 8-oxoGua and its derivatives, summarizes some of the relevant recent DNA repair studies and discusses the mechanisms for metabolism of oxidized guanine derivatives in the (2’-deoxy)ribonucleoside and (2’-deoxy)ribonucleotide pools.

Oxidative Stress in the Pathogenesis of Colorectal Cancer: Cause or Consequence?

“…For example, formation of 8-oxodG in DNA leads to G → T transversions during replication unless the damage is repaired by base excision repair (reviewed in [18]). Recent evidence demonstrates that 8-oxodG in the nucleotide pool can be metabolized to form 8-oxodGTP, which can then incorporates into DNA during cellular replication or during DNA repair leading to A → C transversions [19]. The dGTP nucleotide pool is mainly located in the cytoplasm and is thus more available for attack by ROS in comparison to dG incorporated in DNA, which is located in the nucleous and protected by histones [19].…”

“…Recent evidence demonstrates that 8-oxodG in the nucleotide pool can be metabolized to form 8-oxodGTP, which can then incorporates into DNA during cellular replication or during DNA repair leading to A → C transversions [19]. The dGTP nucleotide pool is mainly located in the cytoplasm and is thus more available for attack by ROS in comparison to dG incorporated in DNA, which is located in the nucleous and protected by histones [19]. Oxidation of DNA may affect DNA methylation due to oxidation of DNA at either the methylated cytosines or guanines in CpG sequences.…”

“…Some of these enzymes are different proteolytic enzymes, glycosylases, endo- and exonucleases, DNA ligases, DNA polymerases, and so forth. For example, repair and removal of DNA containing oxidized bases in vivo are regulated by DNA glycosylases [19], mainly through the base excision repair (BER) although certain types of oxidative lesions also appear to be repaired by nucleotide excision repair (NER) and mismatch repair (MMR) [18]. Cells that possess complex DNA repair system are composed of BER, NER, global genome repair (GGR), and the transcription-coupled repair (TCR) [39].…”

Non-canonical actions of mismatch repair

“…One pathway of lesion formation in DNA would be through incorporation of damaged nucleotides. There has been extensive study of incorporation of oxidized nucleotides, as well as some study of the incorporation of other types of damaged bases [77–83]. MMR could potentially block such incorporation during replication and has been shown to block incorporation of 8-oxoGMP into DNA [84].…”

Endogenously generated DNA nucleobase modifications source, and significance as possible biomarkers of malignant transformation risk, and role in anticancer therapy

“…The products of these repair activities (in addition to maintenance of genomic integrity) are 8-oxoGua, unmodified nucleobases (which can be salvaged and recycled) and, as we have proposed previously, 8-oxodG [31]. Although it appears that the potential exists for these oxidised products to be erroneously reincorporated into DNA [32], the majority ultimately appear in the urine where their measurement is used as a well established, non-invasive biomarker of oxidative stress [31].…”