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Reciprocal Links between RNA Metabolism and DNA Damage
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Reciprocal Links between RNA Metabolism and DNA Damage

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 September 2022) | Viewed by 28940

Special Issue Editor

Dr. Martin Dutertre

E-Mail Website
Guest Editor
Institut Curie – Centre De Recherche, Rue Henri Becquerel, 91401 ORSAY CEDEX, France
Interests: alternative splicing; intronic polyadenylation; DNA damage response; genotoxic agents; cancer chemotherapy

Special Issue Information

Dear Colleagues,

Two central parts of molecular biology are the control of genome integrity and genome expression. The study of genome integrity has largely relied on detailed analyses of the fundamental processes of DNA replication, repair, and recombination and their intimate links between each other and with the cell cycle. Meanwhile, the study of eukaryotic genome expression has revealed that a large part of it—not just genes—is transcribed into a multitude of RNAs, that all the steps of gene expression—from transcription to translation and RNA decay—are regulated, and that multiple steps occur cotranscriptionally, including pre-mRNA degradation, maturation by (alternative) splicing and polyadenylation, subtle modifications like methylation, and release from chromatin.

The past decade has revealed reciprocal links between the control of genome integrity and expression. Firstly, DNA damage widely regulates RNA metabolism, and genes controlling genome integrity are coordinately and specifically regulated at multiple levels of RNA processing. Secondly, the processes of DNA replication and repair on one hand, and the processes of transcription and cotranscriptional RNA processing on the other hand, are connected and reciprocally impact each other in multiple ways. For example, a major source of genome instability is the conflicts between DNA replication and transcription, and defects of cotranscriptional RNA processing can give rise to replication stress and DNA damage. Another example is the increasingly recognized involvement of transcription, noncoding RNAs, RNA–DNA hybrids (R-loops), and RNA-binding proteins in DNA repair and its control. Finally, connections between genome integrity and expression are found in both prokaryotes and eukaryotes, with established or suspected functions in specific cells (e.g., gene recombination in immune cells), the etiology of neurologic and oncologic diseases, and cell responses to therapeutic genotoxic agents.

The aim of this Special Issue is to provide reviews and experimental advances on all aspects pertaining to the links between DNA damage and RNA metabolism, including—but not limited to—their underlying molecular mechanisms, their impact on biological and pathological phenotypes, and the potential insights they provide into additional fields (e.g., mechanisms of genome evolution, virus–host genome interactions).

Dr. Martin Dutertre
Guest Editor

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. Genes 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.

Keywords

  • Genome instability
  • DNA damage
  • Genotoxic agents
  • Transcription–replication conflicts
  • RNA processing
  • Post-transcriptional regulation
  • mRNA translation
  • Noncoding RNAs
  • R-loops
  • RNA-binding proteins

Published Papers (8 papers)

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Editorial

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3 pages, 193 KiB  
Editorial
Editorial for the ‘Reciprocal Links between RNA Metabolism and DNA Damage’ Special Issue: July 2023
by Martin Dutertre
Genes 2023, 14(8), 1570; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14081570 - 01 Aug 2023
Viewed by 805
Abstract
Two central parts of molecular biology are the control of genome integrity and genome expression [...] Full article
(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)

Review

Jump to: Editorial, Other

24 pages, 1523 KiB  
Review
Pathophysiological Role and Diagnostic Potential of R-Loops in Cancer and Beyond
by Essak S. Khan and Sven Danckwardt
Genes 2022, 13(12), 2181; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13122181 - 22 Nov 2022
Cited by 9 | Viewed by 2585
Abstract
R-loops are DNA–RNA hybrids that play multifunctional roles in gene regulation, including replication, transcription, transcription–replication collision, epigenetics, and preserving the integrity of the genome. The aberrant formation and accumulation of unscheduled R-loops can disrupt gene expression and damage DNA, thereby causing genome instability. [...] Read more.
R-loops are DNA–RNA hybrids that play multifunctional roles in gene regulation, including replication, transcription, transcription–replication collision, epigenetics, and preserving the integrity of the genome. The aberrant formation and accumulation of unscheduled R-loops can disrupt gene expression and damage DNA, thereby causing genome instability. Recent links between unscheduled R-loop accumulation and the abundance of proteins that modulate R-loop biogenesis have been associated with numerous human diseases, including various cancers. Although R-loops are not necessarily causative for all disease entities described to date, they can perpetuate and even exacerbate the initially disease-eliciting pathophysiology, making them structures of interest for molecular diagnostics. In this review, we discuss the (patho) physiological role of R-loops in health and disease, their surprising diagnostic potential, and state-of-the-art techniques for their detection. Full article
(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)
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13 pages, 683 KiB  
Review
DNA Damage-Induced RNAPII Degradation and Its Consequences in Gene Expression
by Juan Cristobal Muñoz, Inés Beckerman, Ramveer Choudhary, León Alberto Bouvier and Manuel J. Muñoz
Genes 2022, 13(11), 1951; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13111951 - 26 Oct 2022
Cited by 3 | Viewed by 2021
Abstract
RPB1, the major and catalytic subunit of human RNA Polymerase II (RNAPII), is specifically degraded by the ubiquitin–proteasome system upon induction of DNA damage by different agents, such as ultraviolet (UV) light. The “last resort” model of RNAPII degradation states that a persistently [...] Read more.
RPB1, the major and catalytic subunit of human RNA Polymerase II (RNAPII), is specifically degraded by the ubiquitin–proteasome system upon induction of DNA damage by different agents, such as ultraviolet (UV) light. The “last resort” model of RNAPII degradation states that a persistently stalled RNAPII is degraded at the site of the DNA lesion in order to facilitate access to Nucleotide Excision Repair (NER) factors, thereby promoting repair in template strands of active genes. Recent identification and mutation of the lysine residue involved in RPB1 ubiquitylation and degradation unveiled the relevance of RNAPII levels in the control of gene expression. Inhibition of RNAPII degradation after UV light exposure enhanced RNAPII loading onto chromatin, demonstrating that the mere concentration of RNAPII shapes the gene expression response. In this review, we discuss the role of RNAPII ubiquitylation in NER-dependent repair, recent advances in RPB1 degradation mechanisms and its consequences in gene expression under stress, both in normal and repair deficient cells. Full article
(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)
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11 pages, 1421 KiB  
Review
DNA Damage Response and Cell Cycle Regulation in Pluripotent Stem Cells
by Andy Chun Hang Chen, Qian Peng, Sze Wan Fong, Kai Chuen Lee, William Shu Biu Yeung and Yin Lau Lee
Genes 2021, 12(10), 1548; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101548 - 29 Sep 2021
Cited by 11 | Viewed by 3671
Abstract
Pluripotent stem cells (PSCs) hold great promise in cell-based therapy because of their pluripotent property and the ability to proliferate indefinitely. Embryonic stem cells (ESCs) derived from inner cell mass (ICM) possess unique cell cycle control with shortened G1 phase. In addition, ESCs [...] Read more.
Pluripotent stem cells (PSCs) hold great promise in cell-based therapy because of their pluripotent property and the ability to proliferate indefinitely. Embryonic stem cells (ESCs) derived from inner cell mass (ICM) possess unique cell cycle control with shortened G1 phase. In addition, ESCs have high expression of homologous recombination (HR)-related proteins, which repair double-strand breaks (DSBs) through HR or the non-homologous end joining (NHEJ) pathway. On the other hand, the generation of induced pluripotent stem cells (iPSCs) by forced expression of transcription factors (Oct4, Sox2, Klf4, c-Myc) is accompanied by oxidative stress and DNA damage. The DNA repair mechanism of DSBs is therefore critical in determining the genomic stability and efficiency of iPSCs generation. Maintaining genomic stability in PSCs plays a pivotal role in the proliferation and pluripotency of PSCs. In terms of therapeutic application, genomic stability is the key to reducing the risks of cancer development due to abnormal cell replication. Over the years, we and other groups have identified important regulators of DNA damage response in PSCs, including FOXM1, SIRT1 and PUMA. They function through transcription regulation of downstream targets (P53, CDK1) that are involved in cell cycle regulations. Here, we review the fundamental links between the PSC-specific HR process and DNA damage response, with a focus on the roles of FOXM1 and SIRT1 on maintaining genomic integrity. Full article
(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)
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22 pages, 788 KiB  
Review
Home and Away: The Role of Non-Coding RNA in Intracellular and Intercellular DNA Damage Response
by Annabelle Shaw and Monika Gullerova
Genes 2021, 12(10), 1475; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101475 - 23 Sep 2021
Cited by 14 | Viewed by 3729
Abstract
Non-coding RNA (ncRNA) has recently emerged as a vital component of the DNA damage response (DDR), which was previously believed to be solely regulated by proteins. Many species of ncRNA can directly or indirectly influence DDR and enhance DNA repair, particularly in response [...] Read more.
Non-coding RNA (ncRNA) has recently emerged as a vital component of the DNA damage response (DDR), which was previously believed to be solely regulated by proteins. Many species of ncRNA can directly or indirectly influence DDR and enhance DNA repair, particularly in response to double-strand DNA breaks, which may hold therapeutic potential in the context of cancer. These include long non-coding RNA (lncRNA), microRNA, damage-induced lncRNA, DNA damage response small RNA, and DNA:RNA hybrid structures, which can be categorised as cis or trans based on the location of their synthesis relative to DNA damage sites. Mechanisms of RNA-dependent DDR include the recruitment or scaffolding of repair factors at DNA break sites, the regulation of repair factor expression, and the stabilisation of repair intermediates. DDR can also be communicated intercellularly via exosomes, leading to bystander responses in healthy neighbour cells to generate a population-wide response to damage. Many microRNA species have been directly implicated in the propagation of bystander DNA damage, autophagy, and radioresistance, which may prove significant for enhancing cancer treatment via radiotherapy. Here, we review recent developments centred around ncRNA and their contributions to intracellular and intercellular DDR mechanisms. Full article
(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)
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12 pages, 1073 KiB  
Review
DEAD-Box RNA Helicases and Genome Stability
by Michael Cargill, Rasika Venkataraman and Stanley Lee
Genes 2021, 12(10), 1471; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101471 - 23 Sep 2021
Cited by 40 | Viewed by 7318
Abstract
DEAD-box RNA helicases are important regulators of RNA metabolism and have been implicated in the development of cancer. Interestingly, these helicases constitute a major recurring family of RNA-binding proteins important for protecting the genome. Current studies have provided insight into the connection between [...] Read more.
DEAD-box RNA helicases are important regulators of RNA metabolism and have been implicated in the development of cancer. Interestingly, these helicases constitute a major recurring family of RNA-binding proteins important for protecting the genome. Current studies have provided insight into the connection between genomic stability and several DEAD-box RNA helicase family proteins including DDX1, DDX3X, DDX5, DDX19, DDX21, DDX39B, and DDX41. For each helicase, we have reviewed evidence supporting their role in protecting the genome and their suggested mechanisms. Such helicases regulate the expression of factors promoting genomic stability, prevent DNA damage, and can participate directly in the response and repair of DNA damage. Finally, we summarized the pathological and therapeutic relationship between DEAD-box RNA helicases and cancer with respect to their novel role in genome stability. Full article
(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)
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16 pages, 1417 KiB  
Review
p53 mRNA Metabolism Links with the DNA Damage Response
by Sivakumar Vadivel Gnanasundram, Ondrej Bonczek, Lixiao Wang, Sa Chen and Robin Fahraeus
Genes 2021, 12(9), 1446; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091446 - 20 Sep 2021
Cited by 12 | Viewed by 5867
Abstract
Human cells are subjected to continuous challenges by different genotoxic stress attacks. DNA damage leads to erroneous mutations, which can alter the function of oncogenes or tumor suppressors, resulting in cancer development. To circumvent this, cells activate the DNA damage response (DDR), which [...] Read more.
Human cells are subjected to continuous challenges by different genotoxic stress attacks. DNA damage leads to erroneous mutations, which can alter the function of oncogenes or tumor suppressors, resulting in cancer development. To circumvent this, cells activate the DNA damage response (DDR), which mainly involves cell cycle regulation and DNA repair processes. The tumor suppressor p53 plays a pivotal role in the DDR by halting the cell cycle and facilitating the DNA repair processes. Various pathways and factors participating in the detection and repair of DNA have been described, including scores of RNA-binding proteins (RBPs) and RNAs. It has become increasingly clear that p53’s role is multitasking, and p53 mRNA regulation plays a prominent part in the DDR. This review is aimed at covering the p53 RNA metabolism linked to the DDR and highlights the recent findings. Full article
(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)
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Other

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10 pages, 2284 KiB  
Hypothesis
Microsatellite Instability and Aberrant Pre-mRNA Splicing: How Intimate Is It?
by Laurent Corcos, Enora Le Scanf, Gaël Quéré, Danielle Arzur, Gwennina Cueff, Catherine Le Jossic-Corcos and Cédric Le Maréchal
Genes 2023, 14(2), 311; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14020311 - 25 Jan 2023
Cited by 1 | Viewed by 1368
Abstract
Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by inactivation, through the mutation or epigenetic silencing of one or several genes from the DNA MisMatch [...] Read more.
Cancers that belong to the microsatellite instability (MSI) class can account for up to 15% of all cancers of the digestive tract. These cancers are characterized by inactivation, through the mutation or epigenetic silencing of one or several genes from the DNA MisMatch Repair (MMR) machinery, including MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2 and Exo1. The unrepaired DNA replication errors turn into mutations at several thousand sites that contain repetitive sequences, mainly mono- or dinucleotides, and some of them are related to Lynch syndrome, a predisposition condition linked to a germline mutation in one of these genes. In addition, some mutations shortening the microsatellite (MS) stretch could occur in the 3′-intronic regions, i.e., in the ATM (ATM serine/threonine kinase), MRE11 (MRE11 homolog) or the HSP110 (Heat shock protein family H) genes. In these three cases, aberrant pre-mRNA splicing was observed, and it was characterized by the occurrence of selective exon skipping in mature mRNAs. Because both the ATM and MRE11 genes, which as act as players in the MNR (MRE11/NBS1 (Nibrin)/RAD50 (RAD50 double strand break repair protein) DNA damage repair system, participate in double strand breaks (DSB) repair, their frequent splicing alterations in MSI cancers lead to impaired activity. This reveals the existence of a functional link between the MMR/DSB repair systems and the pre-mRNA splicing machinery, the diverted function of which is the consequence of mutations in the MS sequences. Full article
(This article belongs to the Special Issue Reciprocal Links between RNA Metabolism and DNA Damage)
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