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mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine

Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA, and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positivel...

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Autores principales: Alam, Mahabub, Shima, Hiroki, Matsuo, Yoshitaka, Long, Nguyen Chi, Matsumoto, Mitsuyo, Ishii, Yusho, Sato, Nichika, Sugiyama, Takato, Nobuta, Risa, Hashimoto, Satoshi, Liu, Liang, Kaneko, Mika K., Kato, Yukinari, Inada, Toshifumi, Igarashi, Kazuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243181/
https://www.ncbi.nlm.nih.gov/pubmed/35636512
http://dx.doi.org/10.1016/j.jbc.2022.102084
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author Alam, Mahabub
Shima, Hiroki
Matsuo, Yoshitaka
Long, Nguyen Chi
Matsumoto, Mitsuyo
Ishii, Yusho
Sato, Nichika
Sugiyama, Takato
Nobuta, Risa
Hashimoto, Satoshi
Liu, Liang
Kaneko, Mika K.
Kato, Yukinari
Inada, Toshifumi
Igarashi, Kazuhiko
author_facet Alam, Mahabub
Shima, Hiroki
Matsuo, Yoshitaka
Long, Nguyen Chi
Matsumoto, Mitsuyo
Ishii, Yusho
Sato, Nichika
Sugiyama, Takato
Nobuta, Risa
Hashimoto, Satoshi
Liu, Liang
Kaneko, Mika K.
Kato, Yukinari
Inada, Toshifumi
Igarashi, Kazuhiko
author_sort Alam, Mahabub
collection PubMed
description Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA, and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells; however, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested here whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation via puromycin labeling, we revealed that MAT2A depletion or chemical inhibition reduced protein synthesis in HeLa and Hepa1 cells. Furthermore, overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. In addition, MAT2 inhibition did not accompany reduction in mechanistic target of rapamycin complex 1 activity but nevertheless reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of some fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis; depletion or inhibition of MAT2 reduced 18S rRNA processing. Finally, quantitative mass spectrometry revealed that some translation factors were dynamically methylated in response to the activity of MAT2A. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the levels of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced, whereas it may support proliferation when SAM is sufficient.
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spelling pubmed-92431812022-07-01 mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine Alam, Mahabub Shima, Hiroki Matsuo, Yoshitaka Long, Nguyen Chi Matsumoto, Mitsuyo Ishii, Yusho Sato, Nichika Sugiyama, Takato Nobuta, Risa Hashimoto, Satoshi Liu, Liang Kaneko, Mika K. Kato, Yukinari Inada, Toshifumi Igarashi, Kazuhiko J Biol Chem Research Article Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA, and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells; however, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested here whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation via puromycin labeling, we revealed that MAT2A depletion or chemical inhibition reduced protein synthesis in HeLa and Hepa1 cells. Furthermore, overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. In addition, MAT2 inhibition did not accompany reduction in mechanistic target of rapamycin complex 1 activity but nevertheless reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of some fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis; depletion or inhibition of MAT2 reduced 18S rRNA processing. Finally, quantitative mass spectrometry revealed that some translation factors were dynamically methylated in response to the activity of MAT2A. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the levels of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced, whereas it may support proliferation when SAM is sufficient. American Society for Biochemistry and Molecular Biology 2022-05-27 /pmc/articles/PMC9243181/ /pubmed/35636512 http://dx.doi.org/10.1016/j.jbc.2022.102084 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Alam, Mahabub
Shima, Hiroki
Matsuo, Yoshitaka
Long, Nguyen Chi
Matsumoto, Mitsuyo
Ishii, Yusho
Sato, Nichika
Sugiyama, Takato
Nobuta, Risa
Hashimoto, Satoshi
Liu, Liang
Kaneko, Mika K.
Kato, Yukinari
Inada, Toshifumi
Igarashi, Kazuhiko
mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine
title mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine
title_full mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine
title_fullStr mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine
title_full_unstemmed mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine
title_short mTORC1-independent translation control in mammalian cells by methionine adenosyltransferase 2A and S-adenosylmethionine
title_sort mtorc1-independent translation control in mammalian cells by methionine adenosyltransferase 2a and s-adenosylmethionine
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243181/
https://www.ncbi.nlm.nih.gov/pubmed/35636512
http://dx.doi.org/10.1016/j.jbc.2022.102084
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