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DNA helicases: expression, functions and clinical implications

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195756 Year: Pages: 78 DOI: 10.3389/978-2-88919-575-6 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Genetics
Added to DOAB on : 2015-10-30 16:33:44
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Helicases are the proteins that bind to double- or single-stranded DNA and/or RNA chains to unwind higher order structures, usually consuming energy from the hydrolysis of ATP molecules. The biological roles of helicases are associated with a variety of DNA and/or RNA metabolisms, including DNA-replication, -repair, -recombination, RNA processing, and transcription. Dysfunctions of helicases cause various diseases, such as xeroderma pigmentosum (XP), premature aging syndrome, cancer and immunodeficiency, in humans. Moreover, recent genetic analyses revealed that mutations in helicase-encoding genes are frequently found in patients of specific diseases. Some helicases regulate cellular senescence by controlling integrity of genomes, and others play a role in neuromuscular functions presumably by modulating processing of mRNAs. However, the molecular mechanisms of how helicases are regulated in order to maintain our health are not yet fully understood. In this research topic, we will focus on the expression and functions of helicases and their encoding genes, reviewing recent research progresses that provide new insights into development of clinical and pharmaceutical treatments targeting helicases.

Keywords

Aging --- Cancer --- DNA Repair --- helicases --- Telomere

Molecular mechanisms of cellular stress responses in cancer and their therapeutic implications

Authors: ---
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194964 Year: Pages: 159 DOI: 10.3389/978-2-88919-496-4 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Oncology
Added to DOAB on : 2015-11-16 15:44:59
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In response to stress, cells can activate a myriad of signalling pathways to bring about a specific cellular outcome, including cell cycle arrest, DNA repair, senescence and apoptosis. This response is pivotal for tumour suppression as all of these outcomes result in restriction of the growth and/or elimination of damaged and pre-malignant cells. Thus, a large number of anti-cancer agents target specific components of stress response signalling pathways with the aim of causing tumour regression by stimulating cell death. However, the efficacy of these agents is often impaired due to mutations in genes that are involved in these stress-responsive signalling pathways and instead the oncogenic potential of a cell is increased leading to the initiation and/or progression of tumourigenesis. Moreover, these genetic defects can increase or contribute to resistance to chemotherapeutic agents and/or radiotherapy. Modulating the outcome of cellular stress responses towards cell death in tumour cells without affecting surrounding normal cells is thus one of the ultimate aims in the development of new cancer therapeutics. To achieve this aim, a detailed understanding of cellular stress response pathways and their aberrations in cancer is required.This Research topic aims to reflect the broadness and complexity of this important area of cancer research.

Maintenance of Genome Integrity: DNA Damage Sensing, Signaling, Repair and Replication in Plants

Authors: --- --- --- --- et al.
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889198207 Year: Pages: 129 DOI: 10.3389/978-2-88919-820-7 Language: English
Publisher: Frontiers Media SA
Subject: Botany --- Science (General)
Added to DOAB on : 2016-01-19 14:05:46
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Environmental stresses and metabolic by-products can severely affect the integrity of genetic information by inducing DNA damage and impairing genome stability. As a consequence, plant growth and productivity are irreversibly compromised. To overcome genotoxic injury, plants have evolved complex strategies relying on a highly efficient repair machinery that responds to sophisticated damage perception/signaling networks. The DNA damage signaling network contains several key components: DNA damage sensors, signal transducers, mediators, and effectors. Most of these components are common to other eukaryotes but some features are unique to the plant kingdom. ATM and ATR are well-conserved members of PIKK family, which amplify and transduce signals to downstream effectors. ATM primarily responds to DNA double strand breaks while ATR responds to various forms of DNA damage. The signals from the activated transducer kinases are transmitted to the downstream cell-cycle regulators, such as CHK1, CHK2, and p53 in many eukaryotes. However, plants have no homologue of CHK1, CHK2 nor p53. The finding of Arabidopsis transcription factor SOG1 that seems functionally but not structurally similar to p53 suggests that plants have developed unique cell cycle regulation mechanism. The double strand break repair, recombination repair, postreplication repair, and lesion bypass, have been investigated in several plants. The DNA double strand break, a most critical damage for organisms are repaired non-homologous end joining (NHEJ) or homologous recombination (HR) pathway. Damage on template DNA makes replication stall, which is processed by translesion synthesis (TLS) or error-free postreplication repair (PPR) pathway. Deletion of the error-prone TLS polymerase reduces mutation frequencies, suggesting PPR maintains the stalled replication fork when TLS is not available. Unveiling the regulation networks among these multiple pathways would be the next challenge to be completed. Some intriguing issues have been disclosed such as the cross-talk between DNA repair, senescence and pathogen response and the involvement of non-coding RNAs in global genome stability. Several studies have highlighted the essential contribution of chromatin remodeling in DNA repair. DNA damage sensing, signaling and repair have been investigated in relation to environmental stresses, seed quality issues, mutation breeding in both model and crop plants and all these studies strengthen the idea that components of the plant response to genotoxic stress might represent tools to improve stress tolerance and field performance. This focus issue gives researchers the opportunity to gather and interact by providing Mini-Reviews, Commentaries, Opinions, Original Research and Method articles which describe the most recent advances and future perspectives in the field of DNA damage sensing, signaling and repair in plants. A comprehensive overview of the current progresses dealing with the genotoxic stress response in plants will be provided looking at cellular and molecular level with multidisciplinary approaches. This will hopefully bring together valuable information for both plant biotechnologists and breeders.

Cancer-associated defects in the DNA damage response: drivers for malignant transformation and potential therapeutic targets

Authors: ---
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889199495 Year: Pages: 107 DOI: 10.3389/978-2-88919-949-5 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Genetics
Added to DOAB on : 2016-01-19 14:05:46
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For this eBook, and the associated Research Topic in Frontiers in Genetics, entitled: ‘Cancer-associated defects in the DNA damage response: drivers for malignant transformation and potential therapeutic targets’ we have selected 10 papers that each discusses important, yet distinct aspects of the response to DNA damage in normal cells and cancer cells. Using an evolutionary conserved signaling network called the ‘DNA damage response (DDR)’ cells maintain the integrity of their genome, and thus safeguard cellular functioning and the ability to create viably progeny. Initially, the DDR appeared to consist of few linear kinase-driven pathways. However, research over the past decades in model organisms, as well as in the human system has revealed that the DDR is a complex signaling network, wired by multiple parallel pathways and displaying extensive crosstalk. Besides phosphorylation, multiple other post-translational modifications, including ubiquitination and sumoylation, are involved to achieve chromatin remodeling and initiation of DNA repair. Also, rather than being a cell-intrinsic phenomenon, we increasingly appreciate that cell-cell communication is involved. The recognition and repair of DNA damage is essential to maintain normal physiology. Multiple pathological conditions have been attributed to defective DNA repair, most notably accelerated aging, neurodegeneration and cancer. In the context of cancer, through repair of DNA damage or elimination of irreparably damaged cells, the DDR clearly has a tumor-suppressive role. Indeed, many tumor cells show partially inactivated DDR signaling, which allows proliferation in the context of DNA damage-inducing oncogenes. Simultaneously, loss of specific DDR signaling nodes creates a specific dependence of tumor cells on their remaining DDR components, and thus creates therapeutic opportunities. Especially in the context of cancer treatment, numerous targeted agents are under investigation, either to potentiate the cytotoxic effects of chemo-radiotherapy, or to induce synthetic lethality with cancer-specific alterations, with the treatment of BRCA1/2 mutant cancers with PARP1 inhibitors as a prototype example. We have selected four review articles that provide insight into the key components and the wiring of the DDR and DNA repair. Torgovnick and Schumacher review the involvement of DNA repair in the initiation and treatment of cancer, Brinkmann et al., describe the involvement of ubiquitination in DNA damage signaling and Jaiswal and Lindqvist discuss how cell-extrinsic signaling participates in communication of DNA damage to neighboring cells. In addition, Shatneyeva and colleagues review the connection between the cellular response to DNA damage and escape from immune surveillance. Concerning the therapeutic application of targeting the DDR and DNA repair, three articles were included. Krajewska and van Vugt review the wiring of homologous recombination and how this offers therapeutic opportunities. Additionally, Knittel and colleagues describe how genetic loss of the central DDR component ATM in chronic lymphocytic leukemia can be exploited therapeutically by targeting certain parallel DNA repair pathways. Syljuasen and colleagues report on how targeting of the DDR can be used as a therapeutic strategy in lung cancer. Finally, three chapters describe newly identified regulators of the cellular response to DNA damage. Von Morgen et al. describe the R2TP complex, Lezzi and Fanciluuli review the involvement of Che-1/AATF in the DDR, and Ohms and co-authors describe how retrotransposons are at the basis of increased genomic instability. Altogether, these articles describe how defective responses to DNA damage underlie disease - and especially in the context of cancer -can be exploited to better treat disease.

Grappling with the Multifaceted World of the DNA Damage Response

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889450572 Year: Pages: 306 DOI: 10.3389/978-2-88945-057-2 Language: English
Publisher: Frontiers Media SA
Subject: Genetics --- Science (General)
Added to DOAB on : 2017-07-06 13:27:36
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DNA damage is a major threat to genomic integrity and cell survival. It can arise both spontaneously and in response to exogenous agents. DNA damage can attack most parts of the DNA structure, ranging from minor and major chemical modifications, to single-strand breaks (SSBs) and gaps, to full double-strand breaks (DSBs). If DNA injuries are mis-repaired or unrepaired, they may ultimately result in mutations or wider-scale genome aberrations that threaten cell homeostasis. Consequently, the cells elicit an elaborate signalling network, known as DNA damage response (DDR), to detect and repair these cytotoxic lesions. This Research Topic was aimed at comprehensive investigations of basic and novel mechanisms that underlie the DNA damage response in eukaryotes.DNA damage is a major threat to genomic integrity and cell survival. It can arise both spontaneously and in response to exogenous agents. DNA damage can attack most parts of the DNA structure, ranging from minor and major chemical modifications, to single-strand breaks (SSBs) and gaps, to full double-strand breaks (DSBs). If DNA injuries are mis-repaired or unrepaired, they may ultimately result in mutations or wider-scale genome aberrations that threaten cell homeostasis. Consequently, the cells elicit an elaborate signalling network, known as DNA damage response (DDR), to detect and repair these cytotoxic lesions. This Research Topic was aimed at comprehensive investigations of basic and novel mechanisms that underlie the DNA damage response in eukaryotes.

Chemically-Induced DNA Damage, Mutagenesis, and Cancer

Authors: ---
ISBN: 9783038971290 9783038971306 Year: Pages: X, 264 Language: Englisch
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Biology
Added to DOAB on : 2018-08-27 13:43:27
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Human cancers frequently arise from exposure to chemicals, although radiation, oxidation, and genetic factors play critical roles as well. DNA damage by these agents in a cell is an important first step in the process of carcinogenesis. DNA repair processes have evolved to repair these damages. However, the replication of damaged DNA may occur frequently prior to repair, resulting in gene mutations and the generation of altered proteins. Mutations in an oncogene, a tumor-suppressor gene, or a gene that controls the cell cycle give rise to a clonal cell population with an advantage in proliferation. The complex process of carcinogenesis includes many such events, but has been generally considered to be comprised of the three main stages known as initiation, promotion, and progression, which ultimately give rise to the induction of human cancer. The articles published in this book entitled “Chemically-Induced DNA Damage, Mutagenesis, and Cancer” provide an overview on the topic of the “consequence of DNA damage” in the context of human cancer with their challenges and highlights.

30 years of the Comet Assay: an overview with some new insights

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196494 Year: Pages: 174 DOI: 10.3389/978-2-88919-649-4 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Genetics
Added to DOAB on : 2016-08-16 10:34:25
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By means of this ‘Frontiers in Genetics’ research topic, we are celebrating 30 years of the Comet Assay. The first paper on this single-cell gel electrophoresis assay was published in 1984 by O. Ostling and K.J. Johanson (Biochem. Biophys. Res. Commun. Vol.123: 291-298). The comet assay is a versatile and sensitive method for measuring single - and double-strand breaks in DNA. By including lesion-specific enzymes in the assay, its range and sensitivity are greatly increased, but it is important to bear in mind that their specificity is not absolute. The comet assay (with and without inclusion of lesion-specific enzymes) is widely used as a biomarker assay in human population studies - primarily to measure DNA damage, but increasingly also to assess the capacity of cells for DNA repair. Ostling and Johanson (Biochem. Biophys. Res. Commun., 1984) were also the first to report experiments to measure DNA repair, by simply following the decrease of DNA damage over time after challenging cells with ionising radiation. However, this approach is time-consuming and laborious as it requires an extended period of cell culture and is therefore not ideal for biomonitoring studies, which typically require high-throughput processing of many samples. As an alternative approach, the in vitro comet-based repair assay was developed: a cell extract is incubated with a DNA substrate containing specific lesions, and DNA incisions accumulate. The in vitro comet-based repair assay has been modified and improved over the past decade: it was first devised to measure base excision repair of oxidised purines in lymphocytes (Collins et al., Mutagenesis, 2001), but has since been adapted for other lesions and thus other repair pathways, as well as being applied to tissue samples in addition to cell suspensions. Even after 30 years, the comet assay is still in a growth phase, with many new users each year. Many questions are repeatedly raised, which may seem to have self-evident answers, but clearly, it is necessary to reiterate them for the benefit of the new audience, and sometimes being forced to think again about old topics can shed new light. Different applications of the comet assay are discussed in this special issue, including: genotoxicity testing in different organisms, human biomonitoring, DNA repair studies, environmental biomonitoring and clinical studies. Furthermore, we consider and where possible answer questions, including the ones raised by Raymond Tice at the 8th International Comet Assay Workshop in Perugia (Italy 2009): What is the spectrum of DNA damage detected by the various versions of the comet assay?; What are the limitations associated with each application?; What should be done to standardize the assay for biomonitoring studies?; Can the comet assay be used to monitor changes in global methylation status?; What cell types are suitable for detecting genotoxic substances and their effects in vivo and in vitro?; Can the assay be fully automated?; and more. So this ‘Frontiers in Genetics’ research topic is written for the beginner as well as for the experienced users of the comet assay.

DNA Replication Controls

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ISBN: 9783038425724 9783038425731 Year: Volume: 2 Pages: X, 346 DOI: 10.3390/books978-3-03842-573-1 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Biology
Added to DOAB on : 2017-12-27 08:38:10
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The conditions for DNA replication are not ideal, owing to endogenous and exogenous replication stresses that lead to arrest of the replication fork. Arrested forks are among the most serious threats to genomic integrity because they can break or rearrange, leading to genomic instability, which is a hallmark of cancers and aging-related disorders. This title, “DNA Replication Controls”, presents series of new reviews and original research articles, providing a comprehensive guide to theoretical advancements in the field of DNA replication research in both prokaryotic and eukaryotic systems. The topics include DNA polymerases and helicases; replication initiation; replication timing; replication-associated DNA repair; and replication of difficult-to-replicate genomic regions, including telomeres, centromeres and highly-transcribed regions. This title also provides recent advancements in studies of cellular processes that are coordinated with DNA replication and how defects in the DNA replication program result in genetic disorders, including cancer. Written by leading experts in DNA replication regulation, this book will be an important resource for a wide variety of audiences, including junior graduate students and established investigators who have interests in DNA replication and genome maintenance mechanisms.

DNA Replication Controls

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ISBN: 9783038425687 9783038425694 Year: Volume: 1 Pages: X, 304 DOI: 10.3390/books978-3-03842-569-4 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Biology
Added to DOAB on : 2018-01-02 15:17:59
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The conditions for DNA replication are not ideal, owing to endogenous and exogenous replication stresses that lead to arrest of the replication fork. Arrested forks are among the most serious threats to genomic integrity because they can break or rearrange, leading to genomic instability, which is a hallmark of cancers and aging-related disorders.

Mobile Genetic Elements in Cellular Differentiation, Genome Stability, and Cancer

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889453894 Year: Pages: 123 DOI: 10.3389/978-2-88945-389-4 Language: English
Publisher: Frontiers Media SA
Subject: Biology --- Science (General) --- Chemistry (General)
Added to DOAB on : 2018-11-22 11:50:10
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The human genome, as with the genome of most organisms, is comprised of various types of mobile genetic element derived repeats. Mobile genetic elements that mobilize by an RNA intermediate, include both autonomous and non-autonomous retrotransposons, and mobilize by a “copy and paste” mechanism that relies of the presence of a functional reverse transcriptase activity. The extent to which these different types of elements are actively mobilizing varies among organisms, as revealed with the advent of Next Generation DNA sequencing (NGS).To understand the normal and aberrant mechanisms that impact the mobility of these elements requires a more extensive understanding of how these elements interact with molecular pathways of the cell, including DNA repair, recombination and chromatin. In addition, epigenetic based-mechanisms can also influence the mobility of these elements, likely by transcriptional activation or repression in certain cell types. Studies regarding how mobile genetic elements interface and evolve with these pathways will rely on genomic studies from various model organisms. In addition, the mechanistic details of how these elements are regulated will continue to be elucidated with the use of genetic, biochemical, molecular, cellular, and bioinformatic approaches. Remarkably, the current understanding regarding the biology of these elements in the human genome, suggests these elements may impact developmental biology, including cellular differentiation, neuronal development, and immune function. Thus, aberrant changes in these molecular pathways may also impact disease, including neuronal degeneration, autoimmunity, and cancer.

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