A fly view on the roles and mechanisms of the m⁶A mRNA modification and its players

Figures & data

Figure 1. m⁶A mRNA pathway in vertebrates and Drosophila melanogaster. The m⁶A methyltransferase complex is composed of five factors. In Drosophila, the methyltransferase complex controls neural development and sex determination via its nuclear reader YT521-B. The precise functions or roles of Virilizer and its vertebrate homolog KIAA1429 remain to be identified. No demethlyase has been found so far in Drosophila.

Figure 2. Domain-structure comparison of m⁶A writers and readers between Drosophila and Human. Comparison of the different proteins was based on uniprot (www.uniprot.org). Homology between similar domains was analyzed via protein BLAST from NCBI. Individual domains of Spenito were compared with RBM15; YT521-B with YTHDC1 and CG6422 with YTHDF2 (Hs - homo sapiens, Dm - Drosophila melanogaster).

Table 1. Components of the m⁶A methyltransferase complex and their biologic roles.

METTL3
Human	METTL3	•METTL3 KD leads to circadian clock period elongation.^81
		•METTL3 promotes translation independently of its catalytic activity.^34
		•METTL3 KD prevents differentiation of hESC.^74
Mouse	Mettl3	•Mettl3 KO in naïve mESC leads to hyper naïve ground state, while in primed mESC boost cell differentiation.^32
		•Mettl3 KO leads to embryonic lethality.^32
Zebrafish	METTL3	•Morpholino depletion leads to developmental defects during embryogenesis.^8
A. thaliana	MTA	•MTA disruption results in embryonic lethality.^30
		•MTA reduction leads to various developmental and organ definition defects.^31
S. cerevisiae	Ime4	•Ime4 is required for sporulation and meiosis.^64,82
D. melanogaster	Ime4	•Ime4 inactivation leads to defects during oogenesis.^83
		•Ime4 KO affects fly locomotion due to impaired neuronal function.^21,22
		•Ime4 regulates splicing of Sxl and fine tunes sex determination.^21,22
METTL14
Human	METTL14	•Structural component of the methyltransferase complex.^7,8,11-13
S. cerevisiae	Kar4	•Transcriptional activator required for karyogamy.^35,84
D. melanogaster	Mettl14	•Mettl14 KO affects fly locomotion due to impaired neuronal functions.^22
		•Mettl14 regulates splicing of Sxl and fine tunes sex determination.^21, 22
WTAP
Human	WTAP	•Structural component of the mehyltransferase complex required for METTL3-METTL14 stabilization.^7,8
Mouse	WTAP	•WTAP KO results in early embryonic lethality.^39
Zebrafish	WTAP	•WTAP morpholinos display defects in head and brain development.^8
S. cerevisiae	Mum2	•Mum2 is required for meiotic mRNA methylation as part of the MIS complex (Mum2, Ime4, Slz1).^82
D. melanogaster	Fl(2)d	•Fl(2)d is required for splicing of Sxl and its KO leads to embryonic lethality.^41
		•Fl(2)d controls retinal development.^44
		•Structural component of the methyltransferase complex, required for Ime4-Mettl14 stabilization.^22
RBM15, RBM15B
Human	RBM15,RBM15B	•RBM15 fusion with MKL1 is associated with acute megakaryoblastic leukemia.^50
		•RBM15 and RBM15B are components of the methyltransferase complex, responsible for complex recruitment to targeted sites.^15
Mouse	RBM15, RBM15B	•Loss of RBM15 leads to embryonic lethality.^47
		•RBM15 controls hematopoiesis, B-cell and megakaryocyte differentiation.^47–49
D. melanogaster	Nito	•Nito regulates wingless signaling and photoreceptor development.^51,52
		•Nito is required for splicing of Sxl.^53
		•Component of the methyltransferase complex.^22

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