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Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing.

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Τίτλος: Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing.
Συγγραφείς: Seungjae Lee, Sangmi Lee, Desnick, Robert, Makiko Yasuda, Lai, Eric C.
Πηγή: Science (pre-March 2025); 12/20/2024, Vol. 386 Issue 6728, p1427-1434, 8p, 5 Diagrams
Θεματικοί όροι: Small interfering RNA, Heme, Biosynthesis, Liver cells
Εταιρία/Οντότητα: United States. Food & Drug Administration
Περίληψη: microRNAs (miRNAs) and small interfering RNAs (siRNAs) are 21- to 22-nucleotide RNAs that guide Argonaute-class effectors to targets for repression. In this work, we uncover 5-aminolevulinic acid synthase 1 (ALAS1), the initiating enzyme for heme biosynthesis, as a general repressor of miRNA accumulation. Although heme is known to be a positive cofactor for the nuclear miRNA processing machinery, ALAS1—but not other heme biosynthesis enzymes—limits the assembly and activity of Argonaute complexes under heme-replete conditions. This involves a cytoplasmic role for ALAS1, previously considered inactive outside of mitochondria. Moreover, conditional depletion of ALAS activity from mouse hepatocytes increases miRNAs and enhances siRNA-mediated knockdown. Notably, because ALAS1 is the target of a Food and Drug Administration–approved siRNA drug, agents that suppress ALAS may serve as adjuvants for siRNA therapies. [ABSTRACT FROM AUTHOR]
Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing.
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  Data: <searchLink fieldCode="AR" term="%22Seungjae+Lee%22">Seungjae Lee</searchLink><br /><searchLink fieldCode="AR" term="%22Sangmi+Lee%22">Sangmi Lee</searchLink><br /><searchLink fieldCode="AR" term="%22Desnick%2C+Robert%22">Desnick, Robert</searchLink><br /><searchLink fieldCode="AR" term="%22Makiko+Yasuda%22">Makiko Yasuda</searchLink><br /><searchLink fieldCode="AR" term="%22Lai%2C+Eric+C%2E%22">Lai, Eric C.</searchLink>
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  Data: Science (pre-March 2025); 12/20/2024, Vol. 386 Issue 6728, p1427-1434, 8p, 5 Diagrams
– Name: Subject
  Label: Subject Terms
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  Data: <searchLink fieldCode="DE" term="%22Small+interfering+RNA%22">Small interfering RNA</searchLink><br /><searchLink fieldCode="DE" term="%22Heme%22">Heme</searchLink><br /><searchLink fieldCode="DE" term="%22Biosynthesis%22">Biosynthesis</searchLink><br /><searchLink fieldCode="DE" term="%22Liver+cells%22">Liver cells</searchLink>
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  Data: <searchLink fieldCode="CO" term="%22United+States%2E+Food+%26+Drug+Administration%22">United States. Food & Drug Administration</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: microRNAs (miRNAs) and small interfering RNAs (siRNAs) are 21- to 22-nucleotide RNAs that guide Argonaute-class effectors to targets for repression. In this work, we uncover 5-aminolevulinic acid synthase 1 (ALAS1), the initiating enzyme for heme biosynthesis, as a general repressor of miRNA accumulation. Although heme is known to be a positive cofactor for the nuclear miRNA processing machinery, ALAS1—but not other heme biosynthesis enzymes—limits the assembly and activity of Argonaute complexes under heme-replete conditions. This involves a cytoplasmic role for ALAS1, previously considered inactive outside of mitochondria. Moreover, conditional depletion of ALAS activity from mouse hepatocytes increases miRNAs and enhances siRNA-mediated knockdown. Notably, because ALAS1 is the target of a Food and Drug Administration–approved siRNA drug, agents that suppress ALAS may serve as adjuvants for siRNA therapies. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Science (pre-March 2025) is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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RecordInfo BibRecord:
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    Identifiers:
      – Type: doi
        Value: 10.1126/science.adp9388
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 8
        StartPage: 1427
    Subjects:
      – SubjectFull: United States. Food & Drug Administration
        Type: general
      – SubjectFull: Small interfering RNA
        Type: general
      – SubjectFull: Heme
        Type: general
      – SubjectFull: Biosynthesis
        Type: general
      – SubjectFull: Liver cells
        Type: general
    Titles:
      – TitleFull: Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing.
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            NameFull: Seungjae Lee
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            NameFull: Sangmi Lee
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            NameFull: Desnick, Robert
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            NameFull: Makiko Yasuda
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            NameFull: Lai, Eric C.
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            – D: 20
              M: 12
              Text: 12/20/2024
              Type: published
              Y: 2024
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              Value: 386
            – Type: issue
              Value: 6728
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