Diversity of ribosomes at the level of rRNA variation associated with human health and disease

Rothschild, Daphna; Susanto, Teodorus Theo; Spence, Jeffrey P.; Genuth, Naomi R.; Sinnott-Armstrong, Nasa; Pritchard, Jonathan K.; Barna, Maria

doi:10.1101/2023.01.30.526360

Cited by 10 publications

(7 citation statements)

References 92 publications

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“…This deep coverage across the pre-rRNA gave us the sensitivity to detect very low frequency (<0.05%) edits and any changes in edit frequency between negative control siNT and siAPOBEC3A depletion conditions. While previous studies have observed human rDNA/rRNA variants across rDNA repeats, mature rRNAs, tissues, or individuals (78,85,86) our study allows for identification of variants precisely produced by one enzyme, APOBEC3A.…”

Section: Discussionmentioning

confidence: 95%

The cytidine deaminase APOBEC3A is required for large ribosomal subunit biogenesis

McCool

Bryant

Abriola

et al. 2023

Preprint

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Cancer initiates as a consequence of genomic mutations, and its subsequent progression relies on increased production of ribosomes to maintain high levels of protein synthesis for unchecked cell growth. Recently, cytidine deaminases have been uncovered as sources of mutagenesis in cancer. To form more established connections between these two cancer driving processes, we interrogated the cytidine deaminase family of proteins for potential roles in human ribosome biogenesis. We identified and validated APOBEC3A and APOBEC4 as novel ribosome biogenesis factors through our laboratory's established screening platform for the discovery of regulators of nucleolar function in MCF10A cells. We show that APOBEC3A is required for cell cycle progression and global protein synthesis. More specifically, we highlight APOBEC3A's role within the processing and maturation steps that form the large subunit 5.8S and 28S ribosomal (r)RNAs. Through an innovative nuclear RNA sequencing methodology, we identify candidate APOBEC3A C-to-U editing sites on the pre-rRNA and pre-mRNAs for the first time. Our work reveals the exciting possibility that the pre-rRNA can be edited during its maturation. More broadly, we found an additional function of APOBEC3A in cancer pathology, expanding its relevance as a target for cancer therapeutics.

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Section: Discussionmentioning

confidence: 95%

The cytidine deaminase APOBEC3A is required for large ribosomal subunit biogenesis

McCool

Bryant

Abriola

et al. 2023

Preprint

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“…https://doi.org/10.1038/s41592-024-02181-1 45S rRNA, revealing potentially new ribosome biogenesis components that could have been missed. Another important limitation in our current understanding comes from ignoring the considerable allelic variation that is present within the rRNA sequences of higher eukaryotes, which are known to have notable biological ramifications 66,67 . TREX, due to its sequence-specific nature, can be adapted to study these variations, thus shedding light on their impact on ribosome biogenesis and function.…”

Section: Articlementioning

confidence: 99%

TREX reveals proteins that bind to specific RNA regions in living cells

Dodel,

Guiducci,

Dermit

et al. 2024

Nat Methods

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Different regions of RNA molecules can often engage in specific interactions with distinct RNA-binding proteins (RBPs), giving rise to diverse modalities of RNA regulation and function. However, there are currently no methods for unbiased identification of RBPs that interact with specific RNA regions in living cells and under endogenous settings. Here we introduce TREX (targeted RNase H-mediated extraction of crosslinked RBPs)—a highly sensitive approach for identifying proteins that directly bind to specific RNA regions in living cells. We demonstrate that TREX outperforms existing methods in identifying known interactors of U1 snRNA, and reveals endogenous region-specific interactors of NORAD long noncoding RNA. Using TREX, we generated a comprehensive region-by-region interactome for 45S rRNA, uncovering both established and previously unknown interactions that regulate ribosome biogenesis. With its applicability to different cell types, TREX is an RNA-centric tool for unbiased positional mapping of endogenous RNA–protein interactions in living cells.

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“…At the rRNA level, the mammalian genome contains many different rDNA alleles, which are known to give rise to variant rRNA sequences in different tissue types, but also between individuals [ 121 ]. More recently, a study has shown changes in rRNA sequences between healthy and cancerous biopsy samples [ 122 ] Ribosomal RNA is extensively post-transcriptionally modified, with 2′-O-methylation and pseudouridylation being the most abundant types of modification that can vary between cancer cell lines and tissues, giving rise to heterogeneous ribosomes [ 94 ]. For example, differential rRNA 2′-O-methylation patterns have been identified in a cohort of human breast cancer patients and in patients with diffuse large B cell lymphoma [ 123 , 124 ].…”

Section: A Therapeutic Option Beyond Wnt Signallingmentioning

confidence: 99%

The Role of WNT Pathway Mutations in Cancer Development and an Overview of Therapeutic Options

Groenewald

Lund

Gay

2023

Cells

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It is well established that mutations in the canonical WNT-signalling pathway play a major role in various cancers. Critical to developing new therapeutic strategies is understanding which cancers are driven by WNT pathway activation and at what level these mutations occur within the pathway. Some cancers harbour mutations in genes whose protein products operate at the receptor level of the WNT pathway. For instance, tumours with RNF43 or RSPO mutations, still require exogenous WNT ligands to drive WNT signalling (ligand-dependent mutations). Conversely, mutations within the cytoplasmic segment of the Wnt pathway, such as in APC and CTNNB1, lead to constitutive WNT pathway activation even in the absence of WNT ligands (ligand-independent). Here, we review the predominant driving mutations found in cancer that lead to WNT pathway activation, as well as explore some of the therapeutic interventions currently available against tumours harbouring either ligand-dependent or ligand-independent mutations. Finally, we discuss a potentially new therapeutic avenue by targeting the translational apparatus downstream from WNT signalling.

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Diversity of ribosomes at the level of rRNA variation associated with human health and disease

Cited by 10 publications

References 92 publications

The cytidine deaminase APOBEC3A is required for large ribosomal subunit biogenesis

The cytidine deaminase APOBEC3A is required for large ribosomal subunit biogenesis

TREX reveals proteins that bind to specific RNA regions in living cells

The Role of WNT Pathway Mutations in Cancer Development and an Overview of Therapeutic Options

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