Table 2.

Mechanisms of translation initiation.

Type of mRNA Translation Initiation	Mechanism of Initiation	Description of the Mechanism	Features	Applicability to circRNA Translation	References
Cap-dependent	eIF4E-dependent, with scanning	eIF4E binds the cap structure and the eIF4F complex, then the cap-binding complex recruits the 40S subunit, the initiation complex scans the mRNA until it reaches the start codon, and then the 60S ribosomal subunit joins this complex	The most common, canonical way of translation of mRNAs in higher eukaryotes	Not applicable	[11,12]
	eIF4E-dependent, scanning free	There are several variants of the scanning free mechanism: - mRNA with short 5′-UTR (leaderless mRNA) translation; - translation initiator of short 5′ UTR mediated translation; - Histone H4 translation; - Ribosome shunting	Supposed to be a non-efficient process leading to leaky scanning. At the same time, several reports show efficient and accurate translation of short 5′ UTR mRNAs that are evidently translated differently from the well-known canonical scanning mechanism.	Not applicable	[54]
	eIF4E-independent	DAP5, homolog of eIF4G, which lacks eIF4E binding, forms complexes with eIF3d	About 20% of capped mRNAs are translated this way, during physiological conditions of mTOR inhibition and eIF4E depletion	Not applicable	[55]
Cap-independent	IRES-mediated initiation	IRES interacts with the 43S pre-initiation complex by direct binding via specific structural elements formed with the RNA, indirectly via ITAFs and cellular eIFs or by homology pairing of 5′UTR mRNA motifs with 18S rRNA	The translation efficiency generally is lower than cap-dependent one, but in some cases, it was shown to be equally effective, for example in the case of EMCV	Applicable, data available	[19]
	CITE-mediated	CITEs can be located both within 5′ and 3′ UTRs and bind eIF4E and/or eIF4G subunits of eIF4F. Some CITEs can also directly bind ribosomal subunits, or the ribosomes themselves, without being dependent on elF4F	Translation efficiency of CITEs varies depending on their nature (5′ or 3′ type) and the translated sequence. 3′ CITEs were shown to be an effective substitution of cap-dependent translation	No available data, but theoretically applicable	[56,57]
	m6A-mediated	m6A modification within 5`UTR of mRNA can recruit a 40S ribosomal subunit through direct eIF3 binding	m6A-mediated translation co-exists with eIF4F-mediated translation for a great deal of transcripts, thus fully capped mRNAs can undergo m6A-mediated translation providing selectivity of mRNA translation in response to environmental and physiological conditions	Applicable, data available	[58]
	Mediated by IRES-like structures	Short hexamer sequences in endogenous circRNA are capable of translation initiation	This mechanism is less effective than viral IRESs, but each sequence less than 50 nt may contain a short IRES-like element, thus most human circRNAs might have a potential for translation. However, these structures are not conserved, hardly classified, and hardly predictable	Applicable, data available	[22,33,35]
	Rolling circle amplification translation	Translation initiation of circRNAs carrying only Kozak sequence (without 5′-cap, poly(A), IRES, stop codon) is possible. The ribosome continuously circles the circRNA molecule, which leads to the production of a long repeating peptide	CircRNAs can be efficiently translated by a rolling circle amplification mechanism in a cell-free E. coli translation system and in human cells	Applicable, data available	[50,59]
	R2-mediated	R2 element contains conservative structures (pseudoknots) which can be recognized by the translational machinery	Efficiency depends on the retrotransposon sequence and its structure, some of the R2 elements were shown to be 35 times more effective than HCV IRES	No available data, but theoretically applicable	[60,61]
	Mediated by cis-Acting Sequences and Secondary Structures in 5′ and 3′UTR	The precise mechanism is still unknown, but initiation of translation depends on both secondary structures and primary sequences within UTRs. 5′ and 3′ UTRs of uncapped RNA of Flaviviruses must be free and present in cis	This mechanism was shown for DTMUV, TMUV, DENV2, ZIKA, and JEV, but it is probably common for all Flaviviruses	No available data, most likely not applicable	[62]
	TEE-mediated	Mechanism is unclear	TEE-mediated initiation was described only for the vaccinia virus (VACV)	No available data	[39,40,41]