DNA repair and the origins of urinary oxidized 2'-deoxyribonucleosides

Abstract

Monitoring oxidative stress in vivo is made easier by the ability to use samples obtained non-invasively, such as urine. The analysis of DNA oxidation, by measurement of oxidized 2'-deoxyribonucleosides in urine, particularly 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), has been reported extensively in the literature in many situations relating to various pathologies, populations and environmental exposures. Understanding the origins of urinary 8-oxodG, other than it simply being a marker of DNA oxidation or its synthetic precursors, is important to being able to effectively interpret differences in baseline urinary 8-oxodG levels between subject groups and changes in excretion. Diet and cell turnover play negligible roles in contributing to urinary 8-oxodG levels, leaving DNA repair as a primary source of this lesion. However, which repair processes contribute, and to what extent, to urinary 8-oxodG is still open to question. The most rational source would be the activity of selected members of the Nudix hydrolase family of enzymes, sanitizing the deoxyribonucleotide pool via the degradation of 8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-triphosphate and 8-oxo-7,8-dihydro-2'-deoxyguanosine-5'-diphosphate, yielding mononucleotide products that can then be dephosphorylated to 8-oxodG and excreted. However, nucleotide excision repair (NER), transcription-coupled repair, nucleotide incision repair (NIR), mismatch repair and various exonuclease activities, such as proofreading function associated with DNA polymerases, can all feasibly generate initial products that could yield 8-oxodG after further metabolism. A recent study implying that a significant proportion of genomic 8-oxodG exists in the context of tandem lesions, refractory to repair by glycosylases, suggests the roles of NER and/or NIR remain to be further examined and defined as a source of 8-oxodG. 8-OxodG has been the primary focus of investigation, but other oxidized 2'-deoxyribonucleosides have been detected in urine, 2'-deoxythymidine glycol and 5-hydroxymethyl-2'-deoxyuridine; the origins of these compounds in urine, however, are presently even more speculative than for 8-oxodG.