The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs.
Improper regulation of translation initiation, a vital checkpoint of protein synthesis in the cell, has been linked to a number of cancers. Overexpression of protein subunits of eukaryotic translation initiation factor 3 (eIF3) is associated with increased translation of mRNAs involved in cell proli...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0292080 |
| _version_ | 1797650712051580928 |
|---|---|
| author | Marina P Volegova Cynthia Hermosillo Jamie H D Cate |
| author_facet | Marina P Volegova Cynthia Hermosillo Jamie H D Cate |
| author_sort | Marina P Volegova |
| collection | DOAJ |
| description | Improper regulation of translation initiation, a vital checkpoint of protein synthesis in the cell, has been linked to a number of cancers. Overexpression of protein subunits of eukaryotic translation initiation factor 3 (eIF3) is associated with increased translation of mRNAs involved in cell proliferation. In addition to playing a major role in general translation initiation by serving as a scaffold for the assembly of translation initiation complexes, eIF3 regulates translation of specific cellular mRNAs and viral RNAs. Mutations in the N-terminal Helix-Loop-Helix (HLH) RNA-binding motif of the EIF3A subunit interfere with Hepatitis C Virus Internal Ribosome Entry Site (IRES) mediated translation initiation in vitro. Here we show that the EIF3A HLH motif controls translation of a small set of cellular transcripts enriched in oncogenic mRNAs, including MYC. We demonstrate that the HLH motif of EIF3A acts specifically on the 5' UTR of MYC mRNA and modulates the function of EIF4A1 on select transcripts during translation initiation. In Ramos lymphoma cell lines, which are dependent on MYC overexpression, mutations in the HLH motif greatly reduce MYC expression, impede proliferation and sensitize cells to anti-cancer compounds. These results reveal the potential of the EIF3A HLH motif in eIF3 as a promising chemotherapeutic target. |
| first_indexed | 2024-03-11T16:05:24Z |
| format | Article |
| id | doaj.art-b7dd510be66448b9b3ea87eb5d013fa7 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-03-11T16:05:24Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b7dd510be66448b9b3ea87eb5d013fa72023-10-25T05:31:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01189e029208010.1371/journal.pone.0292080The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs.Marina P VolegovaCynthia HermosilloJamie H D CateImproper regulation of translation initiation, a vital checkpoint of protein synthesis in the cell, has been linked to a number of cancers. Overexpression of protein subunits of eukaryotic translation initiation factor 3 (eIF3) is associated with increased translation of mRNAs involved in cell proliferation. In addition to playing a major role in general translation initiation by serving as a scaffold for the assembly of translation initiation complexes, eIF3 regulates translation of specific cellular mRNAs and viral RNAs. Mutations in the N-terminal Helix-Loop-Helix (HLH) RNA-binding motif of the EIF3A subunit interfere with Hepatitis C Virus Internal Ribosome Entry Site (IRES) mediated translation initiation in vitro. Here we show that the EIF3A HLH motif controls translation of a small set of cellular transcripts enriched in oncogenic mRNAs, including MYC. We demonstrate that the HLH motif of EIF3A acts specifically on the 5' UTR of MYC mRNA and modulates the function of EIF4A1 on select transcripts during translation initiation. In Ramos lymphoma cell lines, which are dependent on MYC overexpression, mutations in the HLH motif greatly reduce MYC expression, impede proliferation and sensitize cells to anti-cancer compounds. These results reveal the potential of the EIF3A HLH motif in eIF3 as a promising chemotherapeutic target.https://doi.org/10.1371/journal.pone.0292080 |
| spellingShingle | Marina P Volegova Cynthia Hermosillo Jamie H D Cate The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs. PLoS ONE |
| title | The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs. |
| title_full | The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs. |
| title_fullStr | The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs. |
| title_full_unstemmed | The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs. |
| title_short | The Helix-Loop-Helix motif of human EIF3A regulates translation of proliferative cellular mRNAs. |
| title_sort | helix loop helix motif of human eif3a regulates translation of proliferative cellular mrnas |
| url | https://doi.org/10.1371/journal.pone.0292080 |
| work_keys_str_mv | AT marinapvolegova thehelixloophelixmotifofhumaneif3aregulatestranslationofproliferativecellularmrnas AT cynthiahermosillo thehelixloophelixmotifofhumaneif3aregulatestranslationofproliferativecellularmrnas AT jamiehdcate thehelixloophelixmotifofhumaneif3aregulatestranslationofproliferativecellularmrnas AT marinapvolegova helixloophelixmotifofhumaneif3aregulatestranslationofproliferativecellularmrnas AT cynthiahermosillo helixloophelixmotifofhumaneif3aregulatestranslationofproliferativecellularmrnas AT jamiehdcate helixloophelixmotifofhumaneif3aregulatestranslationofproliferativecellularmrnas |