Smug1, or Single-strand selective monofunctional uracil DNA glycosylase 1, is a key enzyme in the base excision repair (BER) pathway. It works to remove uracil and certain oxidized bases from DNA, thus playing a crucial role in genome maintenance [1]. Additionally, it has been associated with RNA processing, including the RNA component of telomerase, highlighting its broad biological importance [1]. Genetic models, such as knockout mouse models, have been instrumental in studying its functions.

Using Smug1-knockout mouse models, several significant findings have emerged. In mice, loss of Smug1 leads to increased weight and fat content in one-year-old animals, along with altered enzyme activities related to fatty acid influx and uptake. Lipidomic profiling shows an accumulation of free fatty acids and triglycerides in Smug1-null livers, indicating its role in fat metabolism and development of a fatty liver phenotype [2]. In terms of telomere maintenance, Smug1-knockout cells exhibit telomerase deficiency due to an imbalance in the processing of the telomeric RNA component (hTERC), leading to impaired bone marrow proliferation in knockout mice [3]. Also, Smug1-knockdown and knockout models in hepatocarcinoma HepG2 cells show decreased cell viability, cell cycle arrest in G2/M phases, increased apoptosis, and accumulated DNA damage, suggesting its importance in cell cycle and transcriptional regulation [4].

In conclusion, Smug1 is essential for genome maintenance through its role in BER and has additional functions in RNA processing, fat metabolism, telomere maintenance, cell cycle, and transcriptional regulation. The use of Smug1 knockout mouse models has provided valuable insights into its functions in diseases such as fatty liver disease and potentially in cancer-related processes like those observed in hepatocarcinoma cells [1,2,3,4].

References:

1. Raja, Sripriya, Van Houten, Bennett. 2021. The Multiple Cellular Roles of SMUG1 in Genome Maintenance and Cancer. In International journal of molecular sciences, 22, . doi:10.3390/ijms22041981. https://pubmed.ncbi.nlm.nih.gov/33671338/

2. Carracedo, Sergio, Lirussi, Lisa, Alsøe, Lene, Halvorsen, Bente, Nilsen, Hilde. 2022. SMUG1 regulates fat homeostasis leading to a fatty liver phenotype in mice. In DNA repair, 120, 103410. doi:10.1016/j.dnarep.2022.103410. https://pubmed.ncbi.nlm.nih.gov/36244177/

3. Kroustallaki, Penelope, Lirussi, Lisa, Carracedo, Sergio, Gagos, Sarantis, Nilsen, Hilde. . SMUG1 Promotes Telomere Maintenance through Telomerase RNA Processing. In Cell reports, 28, 1690-1702.e10. doi:10.1016/j.celrep.2019.07.040. https://pubmed.ncbi.nlm.nih.gov/31412240/

4. An, Mi-Jin, Shin, Geun-Seup, Lee, Hyun-Min, Kim, Jung-Woong. 2021. Ablation of SMUG1 Reduces Cell Viability and Increases UVC-Mediated Apoptosis in Hepatocarcinoma HepG2 Cells. In Genes, 12, . doi:10.3390/genes12020201. https://pubmed.ncbi.nlm.nih.gov/33573186/