MBD4, also known as methyl-CpG domain protein 4, encodes a glycosylase that is crucial in the base excision repair (BER) pathway. It is involved in the repair of G:T mismatches resulting from the deamination of 5'-methylcytosine, safeguarding the integrity of the genome. This function is essential for maintaining normal cellular function and preventing the accumulation of mutations that can lead to various diseases [1,2].

Bi-allelic loss-of-function germline variants in MBD4 cause an autosomal recessive multi-tumor predisposition syndrome, increasing the risk of adenomatous colorectal polyposis, acute myeloid leukemia, and uveal melanoma [1]. In colorectal adenomas from MBD4-deficient individuals, a mutator phenotype associated with mutational signature SBS1 was observed, consistent with MBD4's function [1]. In uveal melanoma, MBD4 mutations are associated with a high tumor mutation burden and a CpG>TpG hypermutator phenotype, and MBD4 is a new predisposing gene for this cancer [3]. Additionally, MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients [4]. In chicken DT40 B cells, disruption of the MBD4 uracil glycosylase catalytic region increased somatic hypermutation (SHM) frequency in IgM loss assays, suggesting MBD4 plays a role in SHM [5]. In a switching B cell line, deletion of Mbd4 exons 6 to 8 severely reduced DNA double-strand break (DSB) formation and impaired immunoglobulin heavy chain class switch recombination (CSR), indicating Mbd4 is a component of mismatch repair (MMR)-directed DNA end processing [6].

In conclusion, MBD4 is a key glycosylase in the BER pathway, playing a vital role in maintaining genome integrity. Through gene-knockout or loss-of-function models, it has been shown to be associated with an increased risk of multiple cancers, and is involved in important immunological processes such as SHM and CSR. Understanding MBD4's functions provides insights into disease mechanisms and potential therapeutic strategies, especially in the context of cancer and immune-related diseases.

References:

1. Palles, Claire, West, Hannah D, Chew, Edward, Majewski, Ian J, de Voer, Richarda M. 2022. Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. In American journal of human genetics, 109, 953-960. doi:10.1016/j.ajhg.2022.03.018. https://pubmed.ncbi.nlm.nih.gov/35460607/

2. Sjolund, Ashley B, Senejani, Alireza G, Sweasy, Joann B. 2012. MBD4 and TDG: multifaceted DNA glycosylases with ever expanding biological roles. In Mutation research, 743-744, 12-25. doi:10.1016/j.mrfmmm.2012.11.001. https://pubmed.ncbi.nlm.nih.gov/23195996/

3. Derrien, Anne-Céline, Rodrigues, Manuel, Eeckhoutte, Alexandre, Cassoux, Nathalie, Stern, Marc-Henri. . Germline MBD4 Mutations and Predisposition to Uveal Melanoma. In Journal of the National Cancer Institute, 113, 80-87. doi:10.1093/jnci/djaa047. https://pubmed.ncbi.nlm.nih.gov/32239153/

4. Saint-Ghislain, Mathilde, Derrien, Anne-Céline, Geoffrois, Lionnel, Stern, Marc-Henri, Rodrigues, Manuel. 2022. MBD4 deficiency is predictive of response to immune checkpoint inhibitors in metastatic uveal melanoma patients. In European journal of cancer (Oxford, England : 1990), 173, 105-112. doi:10.1016/j.ejca.2022.06.033. https://pubmed.ncbi.nlm.nih.gov/35863105/

5. Costello, Ryan, Cantillo, Jose F, Kenter, Amy L. 2019. Chicken MBD4 Regulates Immunoglobulin Diversification by Somatic Hypermutation. In Frontiers in immunology, 10, 2540. doi:10.3389/fimmu.2019.02540. https://pubmed.ncbi.nlm.nih.gov/31736964/

6. Grigera, Fernando, Wuerffel, Robert, Kenter, Amy L. 2017. MBD4 Facilitates Immunoglobulin Class Switch Recombination. In Molecular and cellular biology, 37, . doi:10.1128/MCB.00316-16. https://pubmed.ncbi.nlm.nih.gov/27777312/