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Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA–mediated silencing [hepatocyte_sRNA-seq]

ABSTRACT: Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA–mediated silencing [hepatocyte_sRNA-seq]

PROVIDER: PRJNA1088089 | ENA |

REPOSITORIES: ENA

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Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA–mediated silencing [HEK293T_sRNA-seq]

Project description:Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA–mediated silencing [HEK293T_sRNA-seq]

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Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA–mediated silencing [hepatocyte RNA-Seq]

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Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA–mediated silencing [hepatocyte_sRNA-seq]

Project description:RNA interference (RNAi) is a fundamental strategy for gene silencing via small interfering RNAs (siRNAs) that program Argonaute (Ago) effectors, and is related to endogenous silencing via microRNAs (miRNAs). Although most efforts focus on factors that are required for miRNA/RNAi function, biological systems are typically subject to repression. Using molecular genetic approaches, we uncover ALAS1, the first enzyme in the heme biosynthesis pathway, as a repressor of miRNA accumulation in cells and in mice. This was non-intuitive, since heme is known to play a positive role as a cofactor for the nuclear miRNA processing machinery. Instead, we show that ALAS1 (but not other core heme biosynthesis factors) limits RISC assembly and activity. Notably, ALAS1 is the target of one the few current FDA-approved siRNA drugs (Givosiran). Our data have implications for side effects of Givosiran, but also for RNAi therapies in general. We provide evidence that depletion of ALAS1 enhances siRNA-mediated knockdown, suggesting that Givosiran is a viable RNAi adjuvant.

2024-12-19 | GSE261600 | GEO

Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA–mediated silencing [HEK293T_sRNA-seq]

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S-phase independent silencing establishment in Saccharomyces cerevisiae

Project description:S-phase independent silencing establishment in Saccharomyces cerevisiae

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The heme regulatory motifs of heme oxygenase-2 function to transfer heme to the catalytic site for degradation

Project description:Heme regulatory motifs (HRMs) are found in a variety of proteins that are involved in diverse biological functions. In the C-terminal tail region of human heme oxygenase-2 (HO2), there are two HRMs whose cysteines form a disulfide bond; when reduced, these cysteines are available to bind Fe3+-heme. Heme binding to the HRMs is independent of the HO2 catalytic active site in the core of the protein, where heme binds with high affinity and is degraded to biliverdin. Here, we describe the reversible, protein-mediated transfer of heme between the HRMs and the core of HO2. Using HDX-MS to monitor the dynamics of HO2 with and without Fe3+-heme bound to the HRMs and to the core, we detected conformational changes in the catalytic core only in one state of the catalytic cycle – when Fe3+-heme is bound to the HRMs and the core is in the apo state. The conformational changes detected are consistent with transfer of heme between binding sites. Indeed, Fe3+-heme bound to the HRMs is transferred to the apo-core upon either independently expressing the core and a construct spanning the HRM-containing tail or after single turnover of heme at the core. In addition, we observed transfer of heme from the core to the HRMs and equilibration of heme between the core and HRMs. We thus propose a Fe3+-heme transfer model in which heme bound to the HRMs is readily transferred to the catalytic site for degradation to facilitate turnover but can also equilibrate between the sites to maintain heme homeostasis.

2020-03-18 | PXD017538 | Pride

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