Tmt1a-KO Mouse

Tmt1a, formerly known as METTL7A, is a thiol methyltransferase. It has been shown to methylate and inactivate histone deacetylase inhibitors (HDACis) with a thiol as the zinc-binding group, mediating resistance to these drugs. It belongs to the METTL7 family and is responsible for alkyl S-thiol methyl transferase activity in the liver [3]. Its ability to methylate molecules appears to be conserved across species, as seen in rats, mice, chickens, and zebrafish, with amino acid sequence identities of 85.7%, 84.8%, 60.7%, and 51.0% respectively compared to human TMT1A [1,2].

Studies in HEK-293 cells transfected with mouse, rat, chicken, or zebrafish homologs of TMT1A demonstrated that these homologs conferred resistance to thiol-based HDACIs such as NCH-51, KD-5170, and romidepsin, compared to empty vector-transfected cells. They also blunted downstream effects of HDACi treatment like increased p21 expression, increased acetylated histone H3, and cell cycle arrest. Additionally, increased levels of dimethylated romidepsin were found in the culture medium of cells expressing TMT1A homologs after incubation with romidepsin [1,2].

In conclusion, Tmt1a is a conserved thiol methyltransferase with the ability to methylate and inactivate certain HDACis. Its function in conferring resistance to these drugs across species indicates its potential importance in understanding drug-resistance mechanisms in humans. The conservation of its methyltransferase activity suggests that animal models could be valuable in further elucidating its role in human biology and potentially in drug-resistance-related diseases [1,2,3].

References:

1. González Dalmasy, José M, Fitzsimmons, Christina M, Frye, William J E, Robey, Robert W, Gottesman, Michael M. 2023. The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.11.17.567538. https://pubmed.ncbi.nlm.nih.gov/38076968/

2. González Dalmasy, José M, Fitzsimmons, Christina M, Frye, William J E, Robey, Robert W, Gottesman, Michael M. 2024. The thiol methyltransferase activity of TMT1A (METTL7A) is conserved across species. In Chemico-biological interactions, 394, 110989. doi:10.1016/j.cbi.2024.110989. https://pubmed.ncbi.nlm.nih.gov/38574836/

3. Russell, Drake A, Chau, Marvin K, Shi, Yuanyuan, Maldonato, Benjamin J, Totah, Rheem A. 2023. METTL7A (TMT1A) and METTL7B (TMT1B) Are Responsible for Alkyl S-Thiol Methyl Transferase Activity in Liver. In Drug metabolism and disposition: the biological fate of chemicals, 51, 1024-1034. doi:10.1124/dmd.123.001268. https://pubmed.ncbi.nlm.nih.gov/37137720/