*4.3.2 SMUG1*

Single-strand-selective Monofunctional Uracil-DNA Glycosylase (SMUG1) was named so because it was originally thought to prefer ssDNA to dsDNA as a substrate [68]; however, it was later found to be specific for dsDNA [60]. SMUG1 is expressed as a 30 kDa protein and is evenly distributed in the nucleus, accumulates in nucleoli and is also found in the cytosol [59]; additionally, unlike the *UNG* gene, the *SMUG1* gene is not regulated by the cell cycle [69]. Like UNG, SMUG1's substrate specificity is greater for U:G mismatches than U:A pairs; however, the catalytic activity of SMUG1 is slower than UNG's [59]. While SMUG1 has been thought to act as a backup to UNG in SHM and CSR in mice, it is worth noting that mice express higher levels of SMUG1 (relative to UNG) than humans do and that UNG/SMUG1 have different roles in initiating BER in mice vs. humans [60, 70]. In addition to its role as a UDG, SMUG1 is the major DNA glycosylase in removing hydroxymethyluracil (5-hmU, an epigenetic modification [71]) from DNA [59, 72–74], with UNG seemingly not having any significant involvement [75].
