METTL3, or methyltransferase-like 3, is an enzyme that modifies RNA molecules within human cells. It is the primary catalyst for N6-methyladenosine (m6A), a widespread RNA modification. This enzyme’s actions are deeply intertwined with the normal functioning of cells, influencing various biological processes. Understanding its role offers insights into cellular mechanics and broader implications for human health.
The Role of METTL3 in Gene Regulation
METTL3’s main function is adding a methyl group to adenosine bases within RNA, forming N6-methyladenosine (m6A). This modification is one of the most common internal changes found in eukaryotic messenger RNAs (mRNAs), as well as other RNA types like microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The m6A modification occurs within specific sequence motifs, often near stop codons or in the 3′ untranslated regions of mRNA.
This methyltransferase activity is carried out as part of a larger protein complex, with METTL3 as the catalytic subunit. Its partner, METTL14, serves as an RNA-binding scaffold, and proteins like WTAP recruit the complex to specific RNA targets. Once added, the m6A mark influences RNA fate in several ways, affecting its stability, translation into proteins, and even its splicing. For instance, m6A can promote mRNA degradation or enhance its translation, depending on the specific RNA-binding proteins that recognize the modification.
The precise location of m6A modifications and the proteins that “read” these marks determine how gene expression is regulated. This dynamic process allows METTL3 to influence a wide array of cellular functions by altering how genetic information is processed after transcription. Its impact on RNA splicing and stability demonstrates its role in fine-tuning protein production.
METTL3 and Human Health
Proper METTL3 regulation is linked to human health; dysregulation can contribute to various diseases. In cancer, METTL3 often plays a complex role, acting as either a promoter or suppressor of tumor growth, depending on the cancer type. For example, elevated METTL3 expression is observed in cancers like lung adenocarcinoma and gastric cancer, promoting cell proliferation, survival, migration, and invasion. METTL3 can also enhance oncogene translation, such as EGFR and TAZ, further contributing to cancer progression.
METTL3 also impacts neurological disorders and brain function. Its activity is important for normal neurodevelopment, including neurogenesis, learning, and memory. Studies have shown that reduced METTL3 levels or impaired m6A modification in the brain can lead to memory consolidation problems and contribute to neurodegenerative conditions like Alzheimer’s disease. In Alzheimer’s, altered METTL3 expression and distribution are observed in the hippocampus, a brain region important for memory, suggesting its connection to disease pathogenesis.
Beyond cancer and neurological conditions, METTL3 has a significant role in immune responses and inflammatory diseases. It helps maintain the normal function of various immune cells, including monocytes, macrophages, and T cells. For example, METTL3 is upregulated during M1 macrophage activation, which are involved in inflammatory responses, and its overexpression can promote their polarization. Conversely, METTL3 inhibition can stimulate an interferon response, part of the immune system’s defense, by promoting double-stranded RNA formation.
Therapeutic Potential
METTL3’s involvement in various diseases makes it an attractive target for developing new therapies. Researchers are exploring strategies to modulate its activity, particularly in cancers where it acts as a tumor promoter. The well-understood structure of the METTL3/METTL14 complex provides a foundation for designing targeted inhibitors.
Several small-molecule METTL3 inhibitors are currently under investigation. These compounds aim to block the enzyme’s catalytic activity, often by competing with S-adenosylmethionine (SAM), the methyl group donor. Such inhibitors show promise in preclinical models, demonstrating anti-leukemic effects in acute myeloid leukemia by depleting leukemic stem cells without significant toxicity to normal hematopoietic cells.
In non-small cell lung cancer, targeting METTL3 with inhibitors like STM2457 has been shown to increase sensitivity to chemotherapy drugs such as paclitaxel and carboplatin. This suggests that modulating METTL3 could help overcome drug resistance in certain cancers. While METTL3 inhibitor development is early, clinical trials for compounds like STC-15 are underway, indicating significant potential for new therapeutic applications.