Ung-KO Mouse

Ung, short for uracil DNA glycosylase, is a key enzyme in the base excision repair complex. It plays a crucial role in maintaining genomic stability by removing uracils from DNA, initiating high-fidelity base excision repair [2,4]. It is involved in important biological processes such as somatic hypermutation (SHM) and class switch recombination (CSR) during B-cell development [1,2,3,6,8].

In mice, AID deficiency abolishes both CSR and SHM, while UNG-deficient mice have drastically reduced CSR but augmented SHM, suggesting differential functions of UNG in these processes [1]. UNG-RPA interaction mutants in B cells only support high-fidelity repair, with transversions at the Ig variable region abated while CSR is still supported, indicating that this interaction governs the generation of mutations [2]. Also, in the absence of UNG activity, AID-induced damage at telomeres can lead to telomere loss and defective B-cell proliferation, showing that UNG protects B cells from AID-induced telomere loss [5]. Additionally, in C. elegans, ung-1 mutants show a decrease in brood size and lifespan, and an elevated level of germ cell apoptosis when challenged with 5-hydroxymethyluracil, highlighting its role in DNA repair in this organism [7].

In summary, Ung is essential for maintaining genomic integrity through base excision repair, and its functions in processes like SHM, CSR, and protection of B cells from AID-induced telomere loss are revealed through gene-knockout mouse models and other loss-of-function experiments. These studies contribute to understanding the mechanisms underlying antibody diversification and B-cell-related diseases [1,2,5].

References:

1. Yousif, Ashraf S, Stanlie, Andre, Begum, Nasim A, Honjo, Tasuku. 2014. Opinion: uracil DNA glycosylase (UNG) plays distinct and non-canonical roles in somatic hypermutation and class switch recombination. In International immunology, 26, 575-8. doi:10.1093/intimm/dxu071. https://pubmed.ncbi.nlm.nih.gov/24994819/

2. Mu, Yunxiang, Chen, Zaowen, Plummer, Joshua B, Krug, Laurie T, McBride, Kevin M. 2024. UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.04.30.591927. https://pubmed.ncbi.nlm.nih.gov/38746347/

3. Hayran, Abdul B, Liabakk, Nina B, Aas, Per A, Slupphaug, Geir, Kavli, Bodil. . RPA guides UNG to uracil in ssDNA to facilitate antibody class switching and repair of mutagenic uracil at the replication fork. In Nucleic acids research, 52, 784-800. doi:10.1093/nar/gkad1115. https://pubmed.ncbi.nlm.nih.gov/38000394/

4. Krokan, H E, Otterlei, M, Nilsen, H, Aas, P A, Slupphaug, G. . Properties and functions of human uracil-DNA glycosylase from the UNG gene. In Progress in nucleic acid research and molecular biology, 68, 365-86. doi:. https://pubmed.ncbi.nlm.nih.gov/11554311/

5. Cortizas, Elena M, Zahn, Astrid, Safavi, Shiva, Di Noia, Javier M, Verdun, Ramiro E. 2016. UNG protects B cells from AID-induced telomere loss. In The Journal of experimental medicine, 213, 2459-2472. doi:. https://pubmed.ncbi.nlm.nih.gov/27697833/

6. Martin, Ophélie A, Thomas, Morgane, Marquet, Marie, Le Noir, Sandrine, Pinaud, Eric. 2023. The IgH Eµ-MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation. In Frontiers in immunology, 14, 1030813. doi:10.3389/fimmu.2023.1030813. https://pubmed.ncbi.nlm.nih.gov/36865553/

7. Papaluca, Arturo, Wagner, J Richard, Saragovi, H Uri, Ramotar, Dindial. 2018. UNG-1 and APN-1 are the major enzymes to efficiently repair 5-hydroxymethyluracil DNA lesions in C. elegans. In Scientific reports, 8, 6860. doi:10.1038/s41598-018-25124-1. https://pubmed.ncbi.nlm.nih.gov/29717169/

8. Pérez-Durán, Pablo, Belver, Laura, de Yébenes, Virginia G, Pisano, David G, Ramiro, Almudena R. 2012. UNG shapes the specificity of AID-induced somatic hypermutation. In The Journal of experimental medicine, 209, 1379-89. doi:10.1084/jem.20112253. https://pubmed.ncbi.nlm.nih.gov/22665573/