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"SMUG1 - A Classical DNA Glycosylase And An RNA Processing Enzyme"

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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.

References: 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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