Circular RNAs (circRNAs) are a group of non‑coding RNAs, formed mostly through a unique backsplicing mechanism. Originally proposed to be a by‑product from errors in splicing, recent studies have ...shown they exhibit a range of roles in regulating gene expression, including sponging of microRNAs (miRNAs), interactions with RNA‑binding proteins and regulation of transcription. Though research is still in its infancy, evidence suggests circRNA levels are tightly regulated in the cell, reinforced by dysregulated circRNAs levels being implicated in a range of diseases, including cancer and viral infection. There is growing interest in circRNAs playing specific roles in cancers, either oncogenic or as tumour suppressors, with particular focus on their potential as novel biomarkers. This review will provide an overview of circRNA biogenesis and regulation, and their potential roles in the cell, with a focus on their dysregulation in cancer.
Protein tyrosine sulfation (sY) is a post-translational modification (PTM) catalyzed by Golgi-resident tyrosyl protein sulfo transferases (TPSTs). Information on sY in humans is currently limited to ...∼50 proteins, with only a handful having verified sites of sulfation. As such, the contribution of sulfation to the regulation of biological processes remains poorly defined. Mass spectrometry (MS)-based proteomics is the method of choice for PTM analysis but has yet to be applied for systematic investigation of the "sulfome", primarily due to issues associated with discrimination of sY-containing from phosphotyrosine (pY)-containing peptides. In this study, we developed an MS-based workflow for sY-peptide characterization, incorporating optimized Zr
immobilized metal-ion affinity chromatography (IMAC) and TiO
enrichment strategies. Extensive characterization of a panel of sY- and pY-peptides using an array of fragmentation regimes (CID, HCD, EThcD, ETciD, UVPD) highlighted differences in the generation of site-determining product ions and allowed us to develop a strategy for differentiating sulfated peptides from nominally isobaric phosphopeptides based on low collision energy-induced neutral loss. Application of our "sulfomics" workflow to a HEK-293 cell extracellular secretome facilitated identification of 21 new sulfotyrosine-containing proteins, several of which we validate enzymatically, and reveals new interplay between enzymes relevant to both protein and glycan sulfation.
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IJS, KILJ, NUK, PNG, UL, UM
Non‐coding RNA (ncRNA) regulatory networks are emerging as critical regulators of gene expression. These intricate networks of ncRNA:ncRNA interactions modulate multiple cellular pathways and impact ...the development and progression of multiple diseases. Herpesviruses, including Kaposi’s sarcoma‐associated herpesvirus, are adept at utilising ncRNAs, encoding their own as well as dysregulating host ncRNAs to modulate virus gene expression and the host response to infection. Research has mainly focused on unidirectional ncRNA‐mediated regulation of target protein‐coding transcripts; however, we identify a novel host ncRNA regulatory network essential for KSHV lytic replication in B cells. KSHV‐mediated upregulation of the host cell circRNA, circHIPK3, is a key component of this network, functioning as a competing endogenous RNA of miR‐30c, leading to increased levels of the miR‐30c target, DLL4. Dysregulation of this network highlights a novel mechanism of cell cycle control during KSHV lytic replication in B cells. Importantly, disruption at any point within this novel ncRNA regulatory network has a detrimental effect on KSHV lytic replication, highlighting the essential nature of this network and potential for therapeutic intervention.
Synopsis
Lytic replication of Kaposi’s sarcoma‐associated herpesvirus in B cells depends on the dysregulation of a host non‐coding RNA regulatory network. The circular RNA circHIPK3 interferes with the miR‐30c/DLL4 axis to enhance viral lytic replication.
Kaposi’s sarcoma‐associated herpesvirus (KSHV) dysregulates a ncRNA network via upregulation of circHIPK3.
CircHIPK3 is essential for KSHV replication and sponges miR‐29b and miR‐30c.
CircHIPK3 is the key regulator of a miR‐30c/DLL4 axis to influence host cell cycle to enhance KSHV lytic replication.
Lytic replication of Kaposi’s sarcoma‐associated herpesvirus in B cells depends on the dysregulation of a host non‐coding RNA regulatory network. The circular RNA circHIPK3 interferes with the miR‐30c/DLL4 axis to enhance viral lytic replication.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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