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3S-DB: SBP2-Bound RNA Sequencing for the Discovery of Novel Functional SECIS Elements

ABSTRACT: Selenoproteins are defined as proteins that contain selenocysteine (Sec, U), playing crucial roles in living organisms. The incorporation of Sec involves a unique mechanism that primarily includes the UGA codon, the SECIS element, and its binding protein SBP2. Currently, the 25 known human selenoproteins were largely discovered through predictions of stem-looped SECIS structures. However, the exploration of yet-to-be-defined selenoproteins and SECIS elements has been hindered by the accuracy and depth of these predictions. In this study, we focus on SBP2, the core SECIS-binding protein, to analyze all its binding RNAs using RNA immunoprecipitation sequencing (RIP-Seq) technology. Based on this data, we have constructed a robust selenoprotein repository known as the 3S-DB (SBP2-bound RNA sequencing-supported selenoprotein database, SSS-DB or 3S-DB). This 3S-DB contains 1,333 RNA sequences, including all those known selenoprotein RNAs, that can bind to SBP2 with potential SECIS function. Importantly, we validate that the 3' UTRs of PDF and ATP5MJ exhibit SECIS activity. In summary, the established 3S-DB highlights the mRNA that SBP2 can directly bind to, potentially recruiting the entire Sec insertion machinery to generate new selenoproteins. Our results provide a crucial resource for uncovering novel selenoproteins and previously unidentified SECIS elements.

ORGANISM(S): Homo sapiens

PROVIDER: GSE284231 | GEO | 2025/10/12

REPOSITORIES: GEO

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Project description:Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic mutations in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic mutations in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA[Ser]Sec biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the underlying mechanisms of SEPSECS mutations, we generated a novel mouse model recapitulating the respective human pathogenic Y334C mutation in the murine Sepsecs gene (SepsecsY334C). Unlike in patients, homozygous mutant pups died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by inactivating mutations of the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in SepsecsY334C/Y334C mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of SepsecsY334C/Y334C mice with mice harboring a targeted mutation of the catalytically active site Sec to Cys in GPX4 surprisingly rescued perinatal death of SepsecsY334C/Y334C mice, showing that the cardio-respiratory defects of Sepsecs-mutant mice were caused by the lack of GPX4. Like in SepsecsY334C/Y334C mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA[Ser]Sec biosynthesis. Our findings imply that children with mutations in SEPSECS or GPX4 may benefit from treatments partially compensating for impaired GPX4 activity.

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3S-DB: SBP2-Bound RNA Sequencing for the Discovery of Novel Functional SECIS Elements

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