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Biomedicines
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Therapeutic Targeting of RNA Polymerase I Transcription, Ribosome Biogenesis and...
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Therapeutic Targeting of RNA Polymerase I Transcription, Ribosome Biogenesis and Function

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (15 May 2024) | Viewed by 5729

Special Issue Editors

Dr. Denis Drygin

E-Mail Website
Guest Editor
Pimera Therapeutics, 7875 Highland Village Place, Suite 412, San Diego, CA 92129, USA
Interests: RNA; RNA polymerase I; ribosome biogenesis; antisense; siRNA; small molecule; rRNA; ncRNA; microRNA
Prof. Dr. Ross Hannan

E-Mail Website
Guest Editor
The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
Interests: ribosomal RNA; rDNA transcription; RNA polymerase 1; chromatin biology; ribosomopathies; drug development; preclinical models of cancer; early phase clinical trials
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the original late 19th century publication linking nucleolar hypertrophy to carcinogenesis, multiple groups have extensively worked on expanding the knowledge in this field. With two selective inhibitors of RNA polymerase I (Pol I) transcription, CX-5461 and PMR-116 being in clinical development, the promise of the therapeutic targeting of ribosome biogenesis, of which Pol I transcription is a rate-limiting step, is close to be realized.

We welcome original research and review papers, as well as reviews on subjects linking the deregulation of RNA polymerase I (Pol I) transcription and ribosome biogenesis to various pathologies, as well as the potential of compounds that target these processes as therapeutic agents.

We are looking forward to receiving your contributions!

Dr. Denis Drygin
Prof. Dr. Ross Hannan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (3 papers)

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Research

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21 pages, 1970 KiB  
Article
CX-5461 Preferentially Induces Top2α-Dependent DNA Breaks at Ribosomal DNA Loci
by Donald P. Cameron, Jirawas Sornkom, Sameerh Alsahafi, Denis Drygin, Gretchen Poortinga, Grant A. McArthur, Nadine Hein, Ross Hannan and Konstantin I. Panov
Biomedicines 2024, 12(7), 1514; https://doi.org/10.3390/biomedicines12071514 - 8 Jul 2024
Viewed by 1385
Abstract
While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous [...] Read more.
While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous work demonstrating that the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 elicits a non-canonical DNA damage response and our discovery of a critical role for Topoisomerase 2α (Top2α) in the initiation of Pol I-dependent transcription. Here, we identify Top2α as a mediator of CX-5461 response in the murine Eµ-Myc B lymphoma model whereby sensitivity to CX-5461 is dependent on cellular Top2α expression/activity. Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs. Full article
(This article belongs to the Special Issue Therapeutic Targeting of RNA Polymerase I Transcription, Ribosome Biogenesis and Function)
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Review

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14 pages, 983 KiB  
Review
Polymerase I as a Target for Treating Neurodegenerative Disorders
by Mark S. LeDoux
Biomedicines 2024, 12(5), 1092; https://doi.org/10.3390/biomedicines12051092 - 15 May 2024
Viewed by 1435
Abstract
Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to [...] Read more.
Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to consider targeting Pol I or, more generally, rRNA synthesis for the treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins, and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood-onset neuronal death, as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate, and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored. Full article
(This article belongs to the Special Issue Therapeutic Targeting of RNA Polymerase I Transcription, Ribosome Biogenesis and Function)
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14 pages, 1912 KiB  
Review
Decoding Ribosome Heterogeneity: A New Horizon in Cancer Therapy
by Valerio Gelfo, Giulia Venturi, Federico Zacchini and Lorenzo Montanaro
Biomedicines 2024, 12(1), 155; https://doi.org/10.3390/biomedicines12010155 - 11 Jan 2024
Cited by 2 | Viewed by 2438
Abstract
The traditional perception of ribosomes as uniform molecular machines has been revolutionized by recent discoveries, revealing a complex landscape of ribosomal heterogeneity. Opposing the conventional belief in interchangeable ribosomal entities, emerging studies underscore the existence of specialized ribosomes, each possessing unique compositions and [...] Read more.
The traditional perception of ribosomes as uniform molecular machines has been revolutionized by recent discoveries, revealing a complex landscape of ribosomal heterogeneity. Opposing the conventional belief in interchangeable ribosomal entities, emerging studies underscore the existence of specialized ribosomes, each possessing unique compositions and functions. Factors such as cellular and tissue specificity, developmental and physiological states, and external stimuli, including circadian rhythms, significantly influence ribosome compositions. For instance, muscle cells and neurons are characterized by distinct ribosomal protein sets and dynamic behaviors, respectively. Furthermore, alternative forms of ribosomal RNA (rRNAs) and their post-transcriptional modifications add another dimension to this heterogeneity. These variations, orchestrated by spatial, temporal, and conditional factors, enable the manifestation of a broad spectrum of specialized ribosomes, each tailored for potentially distinct functions. Such specialization not only impacts mRNA translation and gene expression but also holds significant implications for broader biological contexts, notably in the realm of cancer research. As the understanding of ribosomal diversity deepens, it also paves the way for exploring novel avenues in cellular function and offers a fresh perspective on the molecular intricacies of translation. Full article
(This article belongs to the Special Issue Therapeutic Targeting of RNA Polymerase I Transcription, Ribosome Biogenesis and Function)
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