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1.
Biosci Rep ; 43(7)2023 07 26.
Article in English | MEDLINE | ID: mdl-37335083

ABSTRACT

Ribosome biogenesis is the complex and essential process that ultimately leads to the synthesis of cellular proteins. Understanding each step of this essential process is imperative to increase our understanding of basic biology, but also more critically, to provide novel therapeutic avenues for genetic and developmental diseases such as ribosomopathies and cancers which can arise when this process is impaired. In recent years, significant advances in technology have made identifying and characterizing novel human regulators of ribosome biogenesis via high-content, high-throughput screens. Additionally, screening platforms have been used to discover novel therapeutics for cancer. These screens have uncovered a wealth of knowledge regarding novel proteins involved in human ribosome biogenesis, from the regulation of the transcription of the ribosomal RNA to global protein synthesis. Specifically, comparing the discovered proteins in these screens showed interesting connections between large ribosomal subunit (LSU) maturation factors and earlier steps in ribosome biogenesis, as well as overall nucleolar integrity. In this review, a discussion of the current standing of screens for human ribosome biogenesis factors through the lens of comparing the datasets and discussing the biological implications of the areas of overlap will be combined with a look toward other technologies and how they can be adapted to discover more factors involved in ribosome synthesis, and answer other outstanding questions in the field.


Subject(s)
Neoplasms , Ribosomes , Humans , Ribosomes/genetics , Ribosomes/metabolism , Protein Biosynthesis , RNA, Ribosomal/genetics , RNA, Ribosomal/metabolism , Cell Nucleolus/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Ribosomal Proteins/genetics
2.
Nat Chem Biol ; 18(6): 643-651, 2022 06.
Article in English | MEDLINE | ID: mdl-35393574

ABSTRACT

Many unannotated microproteins and alternative proteins (alt-proteins) are coencoded with canonical proteins, but few of their functions are known. Motivated by the hypothesis that alt-proteins undergoing regulated synthesis could play important cellular roles, we developed a chemoproteomic pipeline to identify nascent alt-proteins in human cells. We identified 22 actively translated alt-proteins or N-terminal extensions, one of which is post-transcriptionally upregulated by DNA damage stress. We further defined a nucleolar, cell-cycle-regulated alt-protein that negatively regulates assembly of the pre-60S ribosomal subunit (MINAS-60). Depletion of MINAS-60 increases the amount of cytoplasmic 60S ribosomal subunit, upregulating global protein synthesis and cell proliferation. Mechanistically, MINAS-60 represses the rate of late-stage pre-60S assembly and export to the cytoplasm. Together, these results implicate MINAS-60 as a potential checkpoint inhibitor of pre-60S assembly and demonstrate that chemoproteomics enables hypothesis generation for uncharacterized alt-proteins.


Subject(s)
Saccharomyces cerevisiae Proteins , Cell Cycle Proteins/metabolism , Humans , RNA, Ribosomal , Ribosomal Proteins/metabolism , Ribosome Subunits, Large, Eukaryotic/genetics , Ribosome Subunits, Large, Eukaryotic/metabolism , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism
3.
Genes (Basel) ; 12(4)2021 03 29.
Article in English | MEDLINE | ID: mdl-33805424

ABSTRACT

Ribosome biogenesis is a complex process that is responsible for the formation of ribosomes and ultimately global protein synthesis. The first step in this process is the synthesis of the ribosomal RNA in the nucleolus, transcribed by RNA Polymerase I. Historically, abnormal nucleolar structure is indicative of poor cancer prognoses. In recent years, it has been shown that ribosome biogenesis, and rDNA transcription in particular, is dysregulated in cancer cells. Coupled with advancements in screening technology that allowed for the discovery of novel drugs targeting RNA Polymerase I, this transcriptional machinery is an increasingly viable target for cancer therapies. In this review, we discuss ribosome biogenesis in breast cancer and the different cellular pathways involved. Moreover, we discuss current therapeutics that have been found to affect rDNA transcription and more novel drugs that target rDNA transcription machinery as a promising avenue for breast cancer treatment.


Subject(s)
Breast Neoplasms/pathology , DNA, Ribosomal/metabolism , Gene Expression Regulation , RNA, Ribosomal/genetics , Ribosomes/metabolism , Transcription, Genetic , Breast Neoplasms/genetics , DNA, Ribosomal/genetics , Female , Humans , RNA, Ribosomal/metabolism , Ribosomes/genetics
4.
Virol J ; 13: 145, 2016 08 26.
Article in English | MEDLINE | ID: mdl-27565721

ABSTRACT

The Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that transforms B cells and causes several malignancies including Burkitt's lymphoma. EBV differentially expresses at least 49 mature microRNAs (miRNAs) during latency in various infected epithelial and B cells. Recent high-throughput studies and functional assays have begun to reveal the function of the EBV miRNAs suggesting roles in latency, cell cycle control, and apoptosis. In particular, the central executioner of apoptosis, Caspase 3 (CASP3), was proposed as a target of select EBV miRNAs. However, whether CASP3 is truly a target of EBV miRNAs, and if so, which specific miRNAs target CASP3 is still under debate. Based on previously published high-throughput biochemical data and a bioinformatic analysis of the entire CASP3 3'-UTR, we identified 12 EBV miRNAs that have one or more seed binding sites in the CASP3 3'-UTR. We individually tested all 12 miRNAs for repression of CASP3 in luciferase reporter assays, and nine showed statistically significant (P < 0.001) repression of a full-length CASP3 reporter. Further, three EBV miRNAs, including BART22, exhibited repression of endogenous CASP3 protein. These data confirm that CASP3 is a direct target of specific EBV BART miRNAs.


Subject(s)
Caspase 3/metabolism , Epstein-Barr Virus Infections/enzymology , Herpesvirus 4, Human/metabolism , MicroRNAs/metabolism , RNA, Viral/metabolism , Apoptosis , Caspase 3/genetics , Epstein-Barr Virus Infections/genetics , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/genetics , Host-Pathogen Interactions , Humans , MicroRNAs/genetics , RNA, Viral/genetics , Transcription, Genetic , Virus Latency
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