Abstract
Single-strand selective monofunctional uracil DNA glycosylase 1 (SMUG1) works to remove uracil and certain oxidized bases from DNA during base excision repair (BER). This review provides a historical characterization of SMUG1 and 5-hydroxymethyl-2′-deoxyuridine (5-hmdU) one important substrate of this enzyme. Biochemical and structural analyses provide remarkable insight into the mechanism of this glycosylase: SMUG1 has a unique helical wedge that influences damage recognition during repair. Rodent studies suggest that, while SMUG1 shares substrate specificity with another uracil glycosylase UNG2, loss of SMUG1 can have unique cellular phenotypes. This review highlights the multiple roles SMUG1 may play in preserving genome stability, and how the loss of SMUG1 activity may promote cancer. Finally, we discuss recent studies indicating SMUG1 has moonlighting functions beyond BER, playing a critical role in RNA processing including the RNA component of telomerase.
Highlights
Damage to cellular DNA can be generated by both endogenous and exogenous sources, and life has evolved a series of intricate processes for the removal of these potentially mutagenic and carcinogenic injuries [1,2,3]
This review examines one specific glycosylase, single-strand selective monofunctional uracil DNA glycosylase (SMUG1), a protein from the uracil DNA glycosylase (UNG) family of glycosylases, which is responsible for the removal of uracil and oxidized pyrimidines from DNA
We discussed in detail one key protein involved in base excision repair, selective monofunctional uracil DNA glycosylase 1 (SMUG1)
Summary
Damage to cellular DNA can be generated by both endogenous and exogenous sources, and life has evolved a series of intricate processes for the removal of these potentially mutagenic and carcinogenic injuries [1,2,3]. A second important SMUG1 substrate, which occurs at a lower frequency is the deamination product of cytosine, uracil, leading to G:U mismatches [11,12] (Figure 1) Unlike some glycosylases such as thymine DNA glycosylase (TDG), SMUG1 is not cell cycle regulated and is constitutively expressed [13]. Characterization of 5-hmdU formation continued with work from Djurić et al, [21] In this study, both immortalized breast epithelial cells (MCF-10A) and human breast cancer cells (MCF-7) were treated with hydrogen peroxide and 5-hmdU levels were quantified using gas chromatography and mass spectroscopy. The TET-induced formation of 5-hmdU was further investigated by Modrzejewska et al, in 2016 using ultraperformance liquid chromatography mass spectroscopy (UPLCMS/MS) [25] This precise labeling strategy was able to push the detection limits down to one 5-hmdU per 106 deoxynucleotides (dN), comparable to levels of 8-oxoG.
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