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DNA Polymerases and Beyond: Molecular Machines Responding to Replication Stress

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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: closed (31 October 2021) | Viewed by 15748

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Special Issue Editors

Prof. Dr. Giovanni Maga

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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

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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 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. 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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11 pages, 1517 KiB

Open AccessArticle

Detection of Telomeric DNA:RNA Hybrids Using TeloDRIP-qPCR

by Ilaria Rosso and Fabrizio d’Adda di Fagagna

Int. J. Mol. Sci. 2020, 21(24), 9774; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249774 - 21 Dec 2020

Cited by 1 | Viewed by 2925

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) 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

(This article belongs to the Special Issue DNA Polymerases and Beyond: Molecular Machines Responding to Replication Stress)

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Review

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17 pages, 2997 KiB

Open AccessReview

Translesion Synthesis or Repair by Specialized DNA Polymerases Limits Excessive Genomic Instability upon Replication Stress

by Domenico Maiorano, Jana El Etri, Camille Franchet and Jean-Sébastien Hoffmann

Int. J. Mol. Sci. 2021, 22(8), 3924; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083924 - 10 Apr 2021

Cited by 16 | Viewed by 4939

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, 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

(This article belongs to the Special Issue DNA Polymerases and Beyond: Molecular Machines Responding to Replication Stress)

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19 pages, 2605 KiB

Open AccessReview

Products of Oxidative Guanine Damage Form Base Pairs with Guanine

by Katsuhito Kino, Taishu Kawada, Masayo Hirao-Suzuki, Masayuki Morikawa and Hiroshi Miyazawa

Int. J. Mol. Sci. 2020, 21(20), 7645; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207645 - 15 Oct 2020

Cited by 11 | Viewed by 3139

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 (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

(This article belongs to the Special Issue DNA Polymerases and Beyond: Molecular Machines Responding to Replication Stress)

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Graphical abstract

18 pages, 1614 KiB

Open AccessReview

Chromatin Architectural Factors as Safeguards against Excessive Supercoiling during DNA Replication

by Syed Moiz Ahmed and Peter Dröge

Int. J. Mol. Sci. 2020, 21(12), 4504; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124504 - 24 Jun 2020

Cited by 10 | Viewed by 4111

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 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

(This article belongs to the Special Issue DNA Polymerases and Beyond: Molecular Machines Responding to Replication Stress)

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