Enigmatic 5-hydroxymethyluracil: Oxidatively modified base, epigenetic mark or both?

详细信息    查看全文

• 作者：Ryszard Olinski ; ^{ryszardo@cm.umk.pl" class="auth_mail" title="E-mail the corresponding author} ; Marta Starczak ^{marta_koltan@post.pl" class="auth_mail" title="E-mail the corresponding author} ; Daniel Gackowski ^{danielg@cm.umk.pl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：5-caC ; 5-carboxylcytosine ; 5-fC ; 5-formylcytosine ; 5-hmC ; 5-hydroxymethylcytosine ; 5-hmU ; 5-hydroxymethyluracil ; 5-hmdU ; 5-hydroxymethyl-2&prime ; -deoxyuridine ; 5-mC ; 5-methylcytosine ; 8-oxodG ; 8-oxo-7 ; 8-dihydro-2&prime ; -deoxyguanosine ; 8-oxoG ; 8-oxo-7 ; 8-dihydroguanine ; AID/APOBEC ; activation-induced cytidine deaminase ; BER ; base excision repair ; MBD4 ; methyl-binding domain protein 4 ; MUG ; mismatch-specific uracil DNA glycosylase ; NER ; nucleotide excision repair ; ROS ; reactive oxygen species ; SMU
• 刊名：Mutation Research/Reviews in Mutation Research
• 出版年：2016
• 出版时间：January-March 2016
• 年：2016
• 卷：767
• 期：Complete
• 页码：59-66
• 全文大小：1128 K

文摘

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 0.5/10⁶ 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.