Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay
Summary: Developing an effective mRNA therapeutic often requires maximizing protein output per delivered mRNA molecule. We previously found that coding sequence (CDS) design can substantially affect protein output, with mRNA variants containing more optimal codons and higher secondary structure yiel...
| Main Authors: | , , , , , , , , , , , , , , , |
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| 格式: | 文件 |
| 语言: | English |
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Elsevier
2024-04-01
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| 丛编: | Cell Reports |
| 主题: | |
| 在线阅读: | http://www.sciencedirect.com/science/article/pii/S2211124724004261 |
| _version_ | 1827281389471399936 |
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| author | Alicia A. Bicknell David W. Reid Marissa C. Licata Adriana K. Jones Yi Min Cheng Mengying Li Chiaowen Joyce Hsiao Christopher S. Pepin Mihir Metkar Yevgen Levdansky Brian R. Fritz Elizaveta A. Andrianova Ruchi Jain Eugene Valkov Caroline Köhrer Melissa J. Moore |
| author_facet | Alicia A. Bicknell David W. Reid Marissa C. Licata Adriana K. Jones Yi Min Cheng Mengying Li Chiaowen Joyce Hsiao Christopher S. Pepin Mihir Metkar Yevgen Levdansky Brian R. Fritz Elizaveta A. Andrianova Ruchi Jain Eugene Valkov Caroline Köhrer Melissa J. Moore |
| author_sort | Alicia A. Bicknell |
| collection | DOAJ |
| description | Summary: Developing an effective mRNA therapeutic often requires maximizing protein output per delivered mRNA molecule. We previously found that coding sequence (CDS) design can substantially affect protein output, with mRNA variants containing more optimal codons and higher secondary structure yielding the highest protein outputs due to their slow rates of mRNA decay. Here, we demonstrate that CDS-dependent differences in translation initiation and elongation rates lead to differences in translation- and deadenylation-dependent mRNA decay rates, thus explaining the effect of CDS on mRNA half-life. Surprisingly, the most stable and highest-expressing mRNAs in our test set have modest initiation/elongation rates and ribosome loads, leading to minimal translation-dependent mRNA decay. These findings are of potential interest for optimization of protein output from therapeutic mRNAs, which may be achieved by attenuating rather than maximizing ribosome load. |
| first_indexed | 2024-04-24T08:59:45Z |
| format | Article |
| id | doaj.art-7b3fb817ec414bcf9bdcba69344c3e0c |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-24T08:59:45Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7b3fb817ec414bcf9bdcba69344c3e0c2024-04-16T04:09:37ZengElsevierCell Reports2211-12472024-04-01434114098Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decayAlicia A. Bicknell0David W. Reid1Marissa C. Licata2Adriana K. Jones3Yi Min Cheng4Mengying Li5Chiaowen Joyce Hsiao6Christopher S. Pepin7Mihir Metkar8Yevgen Levdansky9Brian R. Fritz10Elizaveta A. Andrianova11Ruchi Jain12Eugene Valkov13Caroline Köhrer14Melissa J. Moore15Moderna, Inc, 325 Binney Street, Cambridge, MA 02142, USA; Corresponding authorModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USARNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USARNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USAModerna, Inc, 325 Binney Street, Cambridge, MA 02142, USA; Corresponding authorSummary: Developing an effective mRNA therapeutic often requires maximizing protein output per delivered mRNA molecule. We previously found that coding sequence (CDS) design can substantially affect protein output, with mRNA variants containing more optimal codons and higher secondary structure yielding the highest protein outputs due to their slow rates of mRNA decay. Here, we demonstrate that CDS-dependent differences in translation initiation and elongation rates lead to differences in translation- and deadenylation-dependent mRNA decay rates, thus explaining the effect of CDS on mRNA half-life. Surprisingly, the most stable and highest-expressing mRNAs in our test set have modest initiation/elongation rates and ribosome loads, leading to minimal translation-dependent mRNA decay. These findings are of potential interest for optimization of protein output from therapeutic mRNAs, which may be achieved by attenuating rather than maximizing ribosome load.http://www.sciencedirect.com/science/article/pii/S2211124724004261CP: Molecular biology |
| spellingShingle | Alicia A. Bicknell David W. Reid Marissa C. Licata Adriana K. Jones Yi Min Cheng Mengying Li Chiaowen Joyce Hsiao Christopher S. Pepin Mihir Metkar Yevgen Levdansky Brian R. Fritz Elizaveta A. Andrianova Ruchi Jain Eugene Valkov Caroline Köhrer Melissa J. Moore Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay Cell Reports CP: Molecular biology |
| title | Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay |
| title_full | Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay |
| title_fullStr | Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay |
| title_full_unstemmed | Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay |
| title_short | Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay |
| title_sort | attenuating ribosome load improves protein output from mrna by limiting translation dependent mrna decay |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724004261 |
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