Abstract
The Wilms tumor 1 (WT1)-associated protein (WTAP) is upregulated in many tumors, including, acute myeloid leukemia (AML), where it plays an oncogenic role by interacting with different proteins involved in RNA processing and cell proliferation. In addition, WTAP is also a regulator of the nuclear complex required for the deposition of N6-methyladenosine (m6A) into mRNAs, containing the METTL3 methyltransferase. However, it is not clear if WTAP may have m6A-independent regulatory functions that might contribute to its oncogenic role. Here, we show that both knockdown and overexpression of METTL3 protein results in WTAP protein upregulation, indicating that METTL3 levels are critical for WTAP protein homeostasis. However, we show that WTAP upregulation is not sufficient to promote cell proliferation in the absence of a functional METTL3. Therein, these data indicate that the reported oncogenic function of WTAP is strictly connected to a functional m6A methylation complex.
Highlights
N6-methyladenosine (m6A) is the most abundant internal chemical modification in eukaryotic mRNA and it can control any aspect of mRNA post-transcriptional regulation[1]
The writer of m6A is a nuclear multicomponent complex composed of two methyltransferase-like proteins, METTL3 and METTL14, and the regulatory proteins Wilms tumor 1-associated protein (WTAP), vir like m6A methyltransferase associated (VIRMA, known as KIAA1429), RNA-binding motif protein 15 (RBM15) and zinc finger CCCH-type containing 13 (ZC3H13)[1, 2]
METTL3 and METTL14 mRNAs are significantly up-regulated in a high percentage of different acute myeloid leukemia (AML) FAB subtypes compared to mature myeloid cells, while both genes are highly expressed in CD34+ progenitor cells (Fig. 1a and Supplemental Figure S1)
Summary
N6-methyladenosine (m6A) is the most abundant internal chemical modification in eukaryotic mRNA and it can control any aspect of mRNA post-transcriptional regulation[1]. Binding of METTL3 and METTL3 APPA to WTAP mRNA in cytoplasm of K562 cells was confirmed by CLIP experiments using stable cell lines carrying inducible FLAG-tagged expression cassettes (Fig. 2d).
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