title: Enigmatic 5-hydroxymethyluracil: Oxidatively modified base, epigenetic mark or both?
abstract: The aim of this review is to describe the reactions which lead to generation of 5-hydroxymethyluracil, as well as the repair processes involved in its removal from DNA, and its level in various cells and urine. 5-hydroxymethyluracil may be formed during the course of the two processes: oxidation/hydroxylation of thymine with resultant formation of 5-hydroxymethyluracil paired with adenine (produced by reactive oxygen species), and reacting of reactive oxygen species with 5-methylcytosine forming 5-hydroxymethylcytosine, followed by its deamination to 5-hydroxymethyluracil mispaired with guanine. However, other, perhaps enzymatic, mechanism(s) may be involved in formation of 5-hydroxymethyluracil mispaired with guanine. Indeed, this mispair may be also formed as a result of deamination of 5-hydroxymethylcytosine, recently described "sixth" DNA base. It was demonstrated that 5-hydroxymethyluracil paired with adenine can be also generated by TET enzymes from thymine during mouse embryonic cell differentiation. Therefore, it is possible that 5-hydroxymethyluracil is epigenetic mark. The level of 5-hydroxymethyluracil in various somatic tissues is relatively stable and resembles that observed in lymphocytes, about 0.5/10(6) dN in human colon, colorectal cancer as well as various rat and porcine tissues. Experimental evidence suggests that SMUG1 and TDG are main enzymes involved in removal of 5-hydroxymethyluracil from DNA. 5-hydroxymethyluracil, in form of 5-hydroxymethyluridine, was also detected in rRNA, and together with SMUG1 may play a role in rRNA quality control. To summarize, 5-hydroxymethyluracil is with no doubt a product of both enzymatic and reactive oxygen species-induced reaction. This modification may probably serve as an epigenetic mark, providing additional layer of information encoded within the genome. However, the pool of 5-hydroxymethyluracil generated as a result of oxidative stress is also likely to disturb physiological epigenetic processes, and as such may be defined as a lesion. Altogether this suggests that 5-hydroxymethyluracil may be either a regulatory or erroneous compound.
authors.affiliation: Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karlowicza 24, Bydgoszcz 85-092, Poland. Electronic address: ryszardo@cm.umk.pl.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Olinski
authors.affiliation: Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karlowicza 24, Bydgoszcz 85-092, Poland. Electronic address: marta_koltan@post.pl.
authors.forename: Marta
authors.initials: M
authors.lastname: Starczak
authors.affiliation: Department of Clinical Biochemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karlowicza 24, Bydgoszcz 85-092, Poland. Electronic address: danielg@cm.umk.pl.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gackowski
mesh_terms: D044503:5-Methylcytosine / Q000737:chemistry; D000818:Animals; D001435:Bacteriophages / Q000235:genetics; D004247:DNA / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D006900:Hydroxylation / Q000502:physiology; D051379:Mice; D010084:Oxidation-Reduction; D010432:Pentoxyl / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013941:Thymine / Q000737:chemistry / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C008055:5-hydroxymethyluracil; D044503:5-Methylcytosine; D010432:Pentoxyl; D004247:DNA; D013941:Thymine
keywords: 5-Hydroxymethylcytosine; 5-Hydroxymethyluracil; Base mispair; Deamination; Epigenetics; Oxidative DNA damage