SMUG1 - A Classical DNA Glycosylase And An RNA Processing Enzyme

Single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1) removes uracil and oxidized pyrimidines, such as 5-hydroxymethyluracil, via the Base Excision Repair (BER) pathway.
Early studies of SMUG1 function suggested that SMUG1 contributed little to repair of uracil in cells proficient for the UNG uracil-DNA glycosylase. I will present recent data from Ung-/-, Smug1-/- and Ung/Smug1-double knockout mice that show a synergistic increase in genomic uracil in the Ung/Smug1-double knockout compared to either single mutant [1]. This suggests that SMUG1 efficiently prevents genomic uracil accumulation, also in the presence of UNG. Whole genome sequencing of UNG/SMUG1-deficient tumours revealed that combined UNG and SMUG1 deficiency leads to the accumulation of mutations, primarily C to T transitions within CpG sequences.
In addition to its classical BER function, SMUG1 interacts with Dyskerin 1 (DKC1) in nucleoli and Cajal bodies and functions in RNA quality control [2]. Consequently, Smug1-/- cells and tissues accumulate hmU in ribosomal RNA. As DKC1 is also a structural component of telomerase and promotes processing and in stabilization of the human telomerase RNA component (TERC), we asked whether SMUG1 is required for telomere maintenance. I will present data that suggest SMUG1 may be involved TERC biogenesis.

1.   Alsoe, L., et al., Uracil Accumulation and Mutagenesis Dominated by Cytosine Deamination in CpG Dinucleotides in Mice Lacking UNG and SMUG1. Sci Rep, 2017. 7(1): p. 7199.
2.   Jobert, L., et al., The human base excision repair enzyme SMUG1 directly interacts with DKC1 and contributes to RNA quality control. Mol Cell, 2013. 49(2): p. 339-45.

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Prof. Wolf Reik
The Cambridge Building - Queen Edith Room