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Special Issue "DNA Polymerases and Beyond: Molecular Machines Responding to Replication Stress"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 October 2021.

Special Issue Editors

Prof. Dr. Giovanni Maga
E-Mail Website
Guest Editor
Head of the DNA Enzymology and Molecular Virology Section, Institute of Molecular Genetics IGM-CNR, National Research Council, via Abbiategrasso 207, I-27100 Pavia, Italy
Interests: genome replication and repair in normal and tumor cells and human viruses; molecular virology; antiviral and anticancer drug development; molecular mechanisms of drug resistance
Dr. Emmanuele Crespan
E-Mail
Guest Editor
DNA Enzymology and Molecular Virology Unit, Institute of Molecular Genetics IGM-CNR, National Research Council, via Abbiategrasso 207, I-27100 Pavia, Italy
Interests: enzymology of DNA replication and repair; tyrosine kinases and proliferative signalling; antiviral and anticancer drug development

Special Issue Information

Dear Colleagues,

The control of the quality and integrity of genetic information as well as its correct duplication are central events for the maintenance of the cell homeostasis. Defects in these processes are at the basis of many pathological conditions, such as cancer, aging, and viral infections. DNA polymerases are at the core of DNA replication and repair pathways, which, however, involve the coordinated action of dozens of other proteins and enzymes. This Special Issue of the International Journal of Molecular Sciences, "DNA Polymerases and Beyond: Molecular Machines Responding to Replication Stress", will focus on the latest advances in understanding the complex network of interactions enabling cells to ensure accurate genome duplication and repair. Authors are invited to submit manuscripts addressing how different molecular steps such as DNA damage recognition and repair, DNA replication fork stalling and restart, and DNA stress signaling and tolerance are interconnected through the action of specialized enzymes and signaling molecules, including non-coding RNAs and metabolic intermediates. We aim at providing the scientific community with a fresh, broad view of the crucial aspects of cell metabolism, to stimulate new avenues of research and the asking of new questions.

Prof. Dr. Giovanni Maga
Dr. Emmanuele Crespan
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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • DNA replication
  • DNA repair
  • Genomic instability
  • DNA repair enzymes
  • DNA damage signaling
  • Non-coding RNAs
  • Cell metabolism

Published Papers (4 papers)

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Research

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Article
Detection of Telomeric DNA:RNA Hybrids Using TeloDRIP-qPCR
Int. J. Mol. Sci. 2020, 21(24), 9774; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249774 - 21 Dec 2020
Viewed by 990
Abstract
Because of their intrinsic characteristics, telomeres are genomic loci that pose significant problems during the replication of the genome. In particular, it has been observed that telomeres that are maintained in cancer cells by the alternative mechanism of the lengthening of telomeres (ALT) [...] Read more.
Because of their intrinsic characteristics, telomeres are genomic loci that pose significant problems during the replication of the genome. In particular, it has been observed that telomeres that are maintained in cancer cells by the alternative mechanism of the lengthening of telomeres (ALT) harbor higher levels of replicative stress compared with telomerase-positive cancer cells. R-loops are three-stranded structures formed by a DNA:RNA hybrid and a displaced ssDNA. Emerging evidence suggests that controlling the levels of R-loops at ALT telomeres is critical for telomere maintenance. In fact, on the one hand, they favor telomere recombination, but on the other, they are a source of detrimental replicative stress. DRIP (DNA:RNA immunoprecipitation) is the main technique used for the detection of R-loops, and it is based on the use of the S9.6 antibody, which recognizes preferentially DNA:RNA hybrids in a sequence-independent manner. The detection of DNA:RNA hybrids in repetitive sequences such as telomeres requires some additional precautions as a result of their repetitive nature. Here, we share an optimized protocol for the detection of telomeric DNA:RNA hybrids, and we demonstrate its application in an ALT and in a telomerase-positive cell line. We demonstrate that ALT telomeres bear higher levels of DNA:RNA hybrids, and we propose this method as a reliable way to detect them in telomeres. Full article
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Review

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Review
Translesion Synthesis or Repair by Specialized DNA Polymerases Limits Excessive Genomic Instability upon Replication Stress
Int. J. Mol. Sci. 2021, 22(8), 3924; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083924 - 10 Apr 2021
Cited by 6 | Viewed by 838
Abstract
DNA can experience “replication stress”, an important source of genome instability, induced by various external or endogenous impediments that slow down or stall DNA synthesis. While genome instability is largely documented to favor both tumor formation and heterogeneity, as well as drug resistance, [...] Read more.
DNA can experience “replication stress”, an important source of genome instability, induced by various external or endogenous impediments that slow down or stall DNA synthesis. While genome instability is largely documented to favor both tumor formation and heterogeneity, as well as drug resistance, conversely, excessive instability appears to suppress tumorigenesis and is associated with improved prognosis. These findings support the view that karyotypic diversity, necessary to adapt to selective pressures, may be limited in tumors so as to reduce the risk of excessive instability. This review aims to highlight the contribution of specialized DNA polymerases in limiting extreme genetic instability by allowing DNA replication to occur even in the presence of DNA damage, to either avoid broken forks or favor their repair after collapse. These mechanisms and their key regulators Rad18 and Polθ not only offer diversity and evolutionary advantage by increasing mutagenic events, but also provide cancer cells with a way to escape anti-cancer therapies that target replication forks. Full article
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Review
Products of Oxidative Guanine Damage Form Base Pairs with Guanine
Int. J. Mol. Sci. 2020, 21(20), 7645; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207645 - 15 Oct 2020
Cited by 1 | Viewed by 737
Abstract
Among the natural bases, guanine is the most oxidizable base. The damage caused by oxidation of guanine, commonly referred to as oxidative guanine damage, results in the formation of several products, including 2,5-diamino-4H-imidazol-4-one (Iz), 2,2,4-triamino-5(2H)-oxazolone (Oz), guanidinoformimine (Gf), guanidinohydantoin/iminoallantoin [...] Read more.
Among the natural bases, guanine is the most oxidizable base. The damage caused by oxidation of guanine, commonly referred to as oxidative guanine damage, results in the formation of several products, including 2,5-diamino-4H-imidazol-4-one (Iz), 2,2,4-triamino-5(2H)-oxazolone (Oz), guanidinoformimine (Gf), guanidinohydantoin/iminoallantoin (Gh/Ia), spiroiminodihydantoin (Sp), 5-carboxamido-5-formamido-2-iminohydantoin (2Ih), urea (Ua), 5-guanidino-4-nitroimidazole (NI), spirodi(iminohydantoin) (5-Si and 8-Si), triazine, the M+7 product, other products by peroxynitrite, alkylated guanines, and 8,5′-cyclo-2′-deoxyguanosine (cG). Herein, we summarize the present knowledge about base pairs containing the products of oxidative guanine damage and guanine. Of these products, Iz is involved in G-C transversions. Oz, Gh/Ia, and Sp form preferably Oz:G, Gh/Ia:G, and Sp:G base pairs in some cases. An involvement of Gf, 2Ih, Ua, 5-Si, 8-Si, triazine, the M+7 product, and 4-hydroxy-2,5-dioxo-imidazolidine-4-carboxylic acid (HICA) in G-C transversions requires further experiments. In addition, we describe base pairs that target the RNA-dependent RNA polymerase (RdRp) of RNA viruses and describe implications for the 2019 novel coronavirus (SARS-CoV-2): When products of oxidative guanine damage are adapted for the ribonucleoside analogs, mimics of oxidative guanine damages, which can form base pairs, may become antiviral agents for SARS-CoV-2. Full article
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Review
Chromatin Architectural Factors as Safeguards against Excessive Supercoiling during DNA Replication
Int. J. Mol. Sci. 2020, 21(12), 4504; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124504 - 24 Jun 2020
Cited by 3 | Viewed by 1380
Abstract
Key DNA transactions, such as genome replication and transcription, rely on the speedy translocation of specialized protein complexes along a double-stranded, right-handed helical template. Physical tethering of these molecular machines during translocation, in conjunction with their internal architectural features, generates DNA topological strain [...] Read more.
Key DNA transactions, such as genome replication and transcription, rely on the speedy translocation of specialized protein complexes along a double-stranded, right-handed helical template. Physical tethering of these molecular machines during translocation, in conjunction with their internal architectural features, generates DNA topological strain in the form of template supercoiling. It is known that the build-up of transient excessive supercoiling poses severe threats to genome function and stability and that highly specialized enzymes—the topoisomerases (TOP)—have evolved to mitigate these threats. Furthermore, due to their intracellular abundance and fast supercoil relaxation rates, it is generally assumed that these enzymes are sufficient in coping with genome-wide bursts of excessive supercoiling. However, the recent discoveries of chromatin architectural factors that play important accessory functions have cast reasonable doubts on this concept. Here, we reviewed the background of these new findings and described emerging models of how these accessory factors contribute to supercoil homeostasis. We focused on DNA replication and the generation of positive (+) supercoiling in front of replisomes, where two accessory factors—GapR and HMGA2—from pro- and eukaryotic cells, respectively, appear to play important roles as sinks for excessive (+) supercoiling by employing a combination of supercoil constrainment and activation of topoisomerases. Looking forward, we expect that additional factors will be identified in the future as part of an expanding cellular repertoire to cope with bursts of topological strain. Furthermore, identifying antagonists that target these accessory factors and work synergistically with clinically relevant topoisomerase inhibitors could become an interesting novel strategy, leading to improved treatment outcomes. Full article
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