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ATP-Independent Initiation during Cap-Independent Translation of m⁶A-Modified mRNA.

ABSTRACT: The methylation of adenosine in the N⁶ position (m⁶A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated in conditions of inhibited cap-dependent translation initiation, e.g., under stress. However, the peculiarities of translation initiation on m⁶A-modified mRNAs are not fully known. In this study, we used toeprinting and translation in a cell-free system to confirm that m⁶A-modified mRNAs can be translated in conditions of suppressed cap-dependent translation. We show for the first time that m⁶A-modified mRNAs display not only decreased elongation, but also a lower efficiency of translation initiation. Additionally, we report relative resistance of m⁶A-mRNA translation initiation in the absence of ATP and inhibited eIF4A activity. Our novel findings indicate that the scanning of m⁶A-modified leader sequences is performed by a noncanonical mechanism.

SUBMITTER: Sakharov PA

PROVIDER: S-EPMC8036370 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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ATP-Independent Initiation during Cap-Independent Translation of m6A-Modified mRNA.

Sakharov Pavel A PA Smolin Egor A EA Lyabin Dmitry N DN Agalarov Sultan C SC

International journal of molecular sciences 20210401 7

The methylation of adenosine in the N6 position (m6A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated in conditions of inhibited cap-dependent translation initiation, e.g., under stress. However, the peculiarities of translation initiation on m6A-modified mRNAs are not fully known. In this study, we used toeprinting ...[more]

PMID: 33915887

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Project description:The human T-cell leukemia virus type 1 (HTLV-1) is a complex human retrovirus that causes adult T cell leukemia and of HTLV-associated myelopathy/tropical spastic paraparesis. The mRNA of some complex retroviruses, including the human and simian immunodeficiency viruses (HIV and SIV), can initiate translation using a canonical cap-dependent mechanism or through an internal ribosome entry site (IRES). In this study, we present strong evidence showing that like HIV-1 and SIV, the 5'-untranslated region (5'UTR) of the HTLV-1 full-length mRNA harbors an IRES. Cap-independent translational activity was evaluated and demonstrated using dual luciferase bicistronic mRNAs in rabbit reticulocyte lysate, in mammalian cell culture, and in Xenopus laevis oocytes. Characterization of the HTLV-1 IRES shows that its activity is dependent on the ribosomal protein S25 (RPS25) and that its function is highly sensitive to the drug edeine. Together, these findings suggest that the 5'UTR of the HTLV-1 full-length mRNA enables internal recruitment of the eukaryotic translation initiation complex. However, the recognition of the initiation codon requires ribosome scanning. These results suggest that, after internal recruitment by the HTLV-1 IRES, a scanning step takes place for the 40S ribosomal subunit to be positioned at the translation initiation codon.The mechanism by which retroviral mRNAs recruit the 40S ribosomal subunit internally is not understood. This study provides new insights into the mechanism of translation initiation used by the human T-cell lymphotropic virus type 1 (HTLV-1). The results show that the HTLV-1 mRNA can initiate translation via a noncanonical mechanism mediated by an internal ribosome entry site (IRES). This study also provides evidence showing the involvement of cellular proteins in HTLV-1 IRES-mediated translation initiation. Together, the data presented in this report significantly contribute to the understanding of HTLV-1 gene expression.

Dataset Information

ATP-Independent Initiation during Cap-Independent Translation of m⁶A-Modified mRNA.

Publications

ATP-Independent Initiation during Cap-Independent Translation of m<sup>6</sup>A-Modified mRNA.

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