Are 8-oxoguanine (8-oxoGua) and 5-hydroxymethyluracil (5-hmUra) oxidatively damaged DNA bases or transcription (epigenetic) marks?
The oxidatively modified DNA base 8-oxo-7,8-dihydroguanine (8-oxoGua) is nontoxic and weakly mutagenic. Here we report on new data suggesting a potential for 8-oxoGua to affect the expression of several genes via epigenetic changes resulting in chromatin relaxation. Using pig thymus extract, we analyzed the distribution of 8-oxoGua among different nuclei fractions representative of transcriptionally active and silenced regions. The levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) found in transcriptionally active euchromatin (4.37/10(6) nucleotides) and in the matrix fraction (4.16/10(6) nucleotides) were about 5 times higher than in transcriptionally silenced heterochromatin (0.91/10(6) nucleotides). Other experimental data are presented which suggest that 8-oxoGua present in specific DNA sequences may be widely used for transcription regulation. Like 8-oxoGua, 5-hydroxymethyluracil (5-hmUra) is another oxidatively modified DNA base (the derivative is formed by thymine oxidation). Recent experimental evidence supports the notion that 5-hmUra plays an important role in active DNA demethylation. This involves overexpression of activation-induced cytidine deaminase (AID) and ten-eleven translocation 1 (TET1) protein (the key proteins involved in active demethylation), which leads to global accumulation of 5-hmUra. Our preliminary data demonstrate a significant increase of the 5-hmUra levels in pig brain extract when compared with liver extract. The lack of 5-hmUra in Escherichia coli DNA also speaks for a role of this modification in the active demethylation process. It is concluded that 8-oxodG and 5-hmUra in DNA may be considered as epigenetic marks.
Department of Clinical Biochemistry, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Karlowicza 24, 85-092 Bydgoszcz, Poland.
Ewelina
E
Zarakowska
Department of Clinical Biochemistry, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Karlowicza 24, 85-092 Bydgoszcz, Poland.
Daniel
D
Gackowski
Department of Clinical Biochemistry, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Karlowicza 24, 85-092 Bydgoszcz, Poland.
Marek
M
Foksinski
Department of Clinical Biochemistry, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Karlowicza 24, 85-092 Bydgoszcz, Poland. Electronic address: ryszardo@cm.umk.pl.
Ryszard
R
Olinski
D000818:Animals; D001921:Brain / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases; D010084:Oxidation-Reduction; D010432:Pentoxyl / Q000031:analogs & derivatives* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013552:Swine; D013941:Thymine / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism
D002843:Chromatin; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D011518:Proto-Oncogene Proteins; C008055:5-hydroxymethyluracil; C024829:8-hydroxyguanine; D006147:Guanine; D010432:Pentoxyl; D004247:DNA; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human; D003564:Cytidine Deaminase; D013941:Thymine
5-hmUra; 8-oxodG; Active DNA demethylation; Epigenetic changes; Gene expression