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.

BRCA1 and BRCA2 protect against oxidative DNA damage converted into double-strand breaks during DNA replication

“…The function of BRCA1 in DNA repair includes homologous recombination, but it also has multiple functions in the cellular response to DNA damage, including contributing to the recruitment of BRCA2. The main repair pathway of oxidized DNA lesions in all cells, from E. coli to human, is base excision repair (BER) [7, 8]. The understanding of breast carcinogenesis in the context of BRCA1- or BRCA2-deficiency suggests that both proteins play a role in the repair of oxidative DNA damage, but not via BER.…”

“…Base excision repair (BER) is the main pathway to repair oxidized DNA lesions in all cells, conserved from E. coli to humans [7, 8]. BER genes are essential in mouse embryonic development, providing housekeeping function for endogenous metabolism that produces oxidative DNA damage.…”

Exposure to Heavy Metals and Polycyclic Aromatic Hydrocarbons and DNA Damage in Taiwanese Traffic Conductors

“…Urinary 8-oxodG in steady state reflects products of DNA damage and repair (35), and could also be regarded as biomarkers of oxidative stress in occupational or environmental fields (6-10). Our results also showed that traffic conductors could have higher levels of urinary 8-oxodG than indoor office workers, which were in agreement with previous studies (7,9).…”

Redox Imbalance in Lung Cancer of Patients with Underlying Chronic Respiratory Conditions

“…Furthermore, the highly reactive species peroxynitrite, formed by the near-diffusion limited reaction between nitric oxide and superoxide anion, may also directly oxidize proteins or nitrate tyrosine residues leading to nitrosative stress. Additionally, the formation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), 2′ a marker of DNA oxidation, was demonstrated to induce mutagenic changes aside from interfering with gene expression (19)(20)(21)(22).…”