scholarly journals Topoisomerase-Mediated DNA Damage in Neurological Disorders

2021 ◽  
Vol 13 ◽  
Author(s):  
Morgan Crewe ◽  
Ram Madabhushi
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Damage Response ◽  
Neurological Disorders ◽  
Neuronal Dysfunction ◽  
Cellular Mechanisms ◽  
Response Factors ◽  
Damage Response ◽  
Potential Sources ◽  
Repair Mechanisms

The nervous system is vulnerable to genomic instability and mutations in DNA damage response factors lead to numerous developmental and progressive neurological disorders. Despite this, the sources and mechanisms of DNA damage that are most relevant to the development of neuronal dysfunction are poorly understood. The identification of primarily neurological abnormalities in patients with mutations in TDP1 and TDP2 suggest that topoisomerase-mediated DNA damage could be an important underlying source of neuronal dysfunction. Here we review the potential sources of topoisomerase-induced DNA damage in neurons, describe the cellular mechanisms that have evolved to repair such damage, and discuss the importance of these repair mechanisms for preventing neurological disorders.

scholarly journals Attenuating the DNA damage response to double-strand breaks restores function in models of CNS neurodegeneration

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Richard I Tuxworth ◽  
Matthew J Taylor ◽  
Ane Martin Anduaga ◽  
Alaa Hussien-Ali ◽  
Sotiroula Chatzimatthaiou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Damage Response ◽  
Neurological Disorders ◽  
Double Strand Breaks ◽  
Strand Breaks ◽  
Damage Response ◽  
Ganglion Neurons

Abstract DNA double-strand breaks are a feature of many acute and long-term neurological disorders, including neurodegeneration, following neurotrauma and after stroke. Persistent activation of the DNA damage response in response to double-strand breaks contributes to neural dysfunction and pathology as it can force post-mitotic neurons to re-enter the cell cycle leading to senescence or apoptosis. Mature, non-dividing neurons may tolerate low levels of DNA damage, in which case muting the DNA damage response might be neuroprotective. Here, we show that attenuating the DNA damage response by targeting the meiotic recombination 11, Rad50, Nijmegen breakage syndrome 1 complex, which is involved in double-strand break recognition, is neuroprotective in three neurodegeneration models in Drosophila and prevents Aβ1-42-induced loss of synapses in embryonic hippocampal neurons. Attenuating the DNA damage response after optic nerve injury is also neuroprotective to retinal ganglion cells and promotes dramatic regeneration of their neurites both in vitro and in vivo. Dorsal root ganglion neurons similarly regenerate when the DNA damage response is targeted in vitro and in vivo and this strategy also induces significant restoration of lost function after spinal cord injury. We conclude that muting the DNA damage response in the nervous system is neuroprotective in multiple neurological disorders. Our results point to new therapies to maintain or repair the nervous system.

scholarly journals Attenuating the DNA damage response to double strand breaks restores function in models of CNS neurodegeneration

2018 ◽  
Author(s):  
Richard I. Tuxworth ◽  
Matthew J. Taylor ◽  
Ane Martin Anduaga ◽  
Alaa Hussien-Ali ◽  
Sotiroula Chatzimatthaiou ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Damage Response ◽  
Neurological Disorders ◽  
Double Strand Breaks ◽  
Strand Breaks ◽  
Damage Response ◽  
Ganglion Neurons

AbstractDNA double-strand breaks are a feature of many acute and long-term neurological disorders, including neurodegeneration, following neurotrauma and after stroke. Persistent activation of the DNA damage response in response to double strand breaks contributes to neural dysfunction and pathology as it can force post-mitotic neurons to re-enter the cell cycle leading to senescence or apoptosis. Mature, non-dividing neurons may tolerate low levels of DNA damage, in which case muting the DNA damage response might be neuroprotective. Here, we show that attenuating the DNA damage response by targeting the meiotic recombination 11, Rad50, Nijmegen breakage syndrome 1 complex, which is involved in double strand break recognition, is neuroprotective in three neurodegeneration models in Drosophila and prevents Aβ1-42-induced loss of synapses in embryonic hippocampal neurons. Attenuating the DNA damage response after optic nerve injury is also neuroprotective to retinal ganglion cells and promotes dramatic regeneration of their neurites both in vitro and in vivo. Dorsal root ganglion neurons similarly regenerate when the DNA damage response is targeted in vitro and in vivo and this strategy also induces significant restoration of lost function after spinal cord injury. We conclude that muting the DNA damage response in the nervous system is neuroprotective in multiple neurological disorders. Our results point to new therapies to maintain or repair the nervous system.

scholarly journals DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 504
Author(s):  
Takayuki Saitoh ◽  
Tsukasa Oda
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Tumor Microenvironment ◽  
Dna Damage Response ◽  
Genetic Instability ◽  
Dna Repair Mechanisms ◽  
Damage Response ◽  
Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

scholarly journals DNA Damage and DNA Damage Response in Chronic Myeloid Leukemia

2020 ◽  
Vol 21 (4) ◽  
pp. 1177 ◽  
Author(s):  
Popp ◽  
Kohl ◽  
Naumann ◽  
Flach ◽  
Brendel ◽  
...  
Keyword(s):  
Dna Damage ◽  
Chronic Myeloid Leukemia ◽  
Dna Damage Response ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Blastic Transformation ◽  
Γh2ax Foci ◽  
Damage Response ◽  
Nhej Repair ◽  
Repair Mechanisms

DNA damage and alterations in the DNA damage response (DDR) are critical sources of genetic instability that might be involved in BCR-ABL1 kinase-mediated blastic transformation of chronic myeloid leukemia (CML). Here, increased DNA damage is detected by γH2AX foci analysis in peripheral blood mononuclear cells (PBMCs) of de novo untreated chronic phase (CP)-CML patients (n = 5; 2.5 γH2AX foci per PBMC ± 0.5) and blast phase (BP)-CML patients (n = 3; 4.4 γH2AX foci per PBMC ± 0.7) as well as CP-CML patients with loss of major molecular response (MMR) (n = 5; 1.8 γH2AX foci per PBMC ± 0.4) when compared to DNA damage in PBMC of healthy donors (n = 8; 1.0 γH2AX foci per PBMC ± 0.1) and CP-CML patients in deep molecular response or MMR (n = 26; 1.0 γH2AX foci per PBMC ± 0.1). Progressive activation of erroneous non-homologous end joining (NHEJ) repair mechanisms during blastic transformation in CML is indicated by abundant co-localization of γH2AX/53BP1 foci, while a decline of the DDR is suggested by defective expression of (p-)ATM and (p-)CHK2. In summary, our data provide evidence for the accumulation of DNA damage in the course of CML and suggest ongoing DNA damage, erroneous NHEJ repair mechanisms, and alterations in the DDR as critical mediators of blastic transformation in CML.

scholarly journals The Intra- and Extra-Telomeric Role of TRF2 in the DNA Damage Response

2021 ◽  
Vol 22 (18) ◽  
pp. 9900
Author(s):  
Siti A. M. Imran ◽  
Muhammad Dain Yazid ◽  
Wei Cui ◽  
Yogeswaran Lokanathan
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Response Factors ◽  
Telomere Repeat ◽  
Protection Mechanism ◽  
Dna Instability ◽  
Binding Factor ◽  
Damage Response ◽  
Dna Break

Telomere repeat binding factor 2 (TRF2) has a well-known function at the telomeres, which acts to protect the telomere end from being recognized as a DNA break or from unwanted recombination. This protection mechanism prevents DNA instability from mutation and subsequent severe diseases caused by the changes in DNA, such as cancer. Since TRF2 actively inhibits the DNA damage response factors from recognizing the telomere end as a DNA break, many more studies have also shown its interactions outside of the telomeres. However, very little has been discovered on the mechanisms involved in these interactions. This review aims to discuss the known function of TRF2 and its interaction with the DNA damage response (DDR) factors at both telomeric and non-telomeric regions. In this review, we will summarize recent progress and findings on the interactions between TRF2 and DDR factors at telomeres and outside of telomeres.

scholarly journals PIMREG expression level predicts glioblastoma patient survival and affects temozolomide resistance and DNA damage response

2021 ◽  
Author(s):  
Rodolfo Bortolozo Serafim ◽  
Cibele Cardoso ◽  
Vanessa Arfelli ◽  
Valeria Valente ◽  
Leticia Fröhlich Archangelo
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Damage Response ◽  
Cellular Proliferation ◽  
Patient Survival ◽  
Glioblastoma Cells ◽  
Damage Response ◽  
Genotoxic Agents ◽  
And Migration ◽  
And Function

Abstract PIMREG expression strongly correlates with cellular proliferation in both malignant and normal cells. Throughout embryo development, PIMREG expression is prominent at the central nervous system. Recent studies have described high levels of PIMREG transcripts in different types of tumors and correlated with patient survival and tumor aggressiveness. Given the emerging significance of PIMREG in carcinogenesis and its putative role in the context of the nervous system, we investigated the expression and function of PIMREG in gliomas, the most common primary brain tumors. We performed an extensive analysis of PIMREG expression in tumors samples of glioma patients, assessed the effects of PIMREG silencing and overexpression on the sensitivity of glioblastoma cell lines treated with genotoxic agents commonly used for treating patients and assessed for treatment response, proliferation and migration. We show that glioblastoma exhibits the highest levels of PIMREG expression among all cancers analyzed and that elevated PIMREG expression is a biomarker for glioma progression and patient outcome. Moreover, PIMREG is induced by genotoxic agents and its silencing renders glioblastoma cells sensitive to temozolomide treatment and affects ATR- and ATM-dependent signaling. Our data demonstrate that PIMREG plays a role in DNA damage response and temozolomide resistance of glioblastoma cells and further support the PIMREG role in tumorigenesis.

Quantitative analysis of DNA-damage response factors after sequential ion microirradiation

2008 ◽  
Vol 47 (4) ◽  
pp. 415-422 ◽  
Author(s):  
Christoph Greubel ◽  
Volker Hable ◽  
Guido A. Drexler ◽  
Andreas Hauptner ◽  
Steffen Dietzel ◽  
...  
Keyword(s):  
Dna Damage ◽  
Quantitative Analysis ◽  
Dna Damage Response ◽  
Response Factors ◽  
Damage Response

scholarly journals Ubiquitylation, neddylation and the DNA damage response

Open Biology ◽  
2015 ◽  
Vol 5 (4) ◽  
pp. 150018 ◽  
Author(s):  
Jessica S. Brown ◽  
Stephen P. Jackson
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Response ◽  
Dna Double Strand Breaks ◽  
Post Translational Modification ◽  
Strand Breaks ◽  
Damage Sensing ◽  
Damage Response ◽  
Repair Mechanisms ◽  
And Function

Failure of accurate DNA damage sensing and repair mechanisms manifests as a variety of human diseases, including neurodegenerative disorders, immunodeficiency, infertility and cancer. The accuracy and efficiency of DNA damage detection and repair, collectively termed the DNA damage response (DDR), requires the recruitment and subsequent post-translational modification (PTM) of a complex network of proteins. Ubiquitin and the ubiquitin-like protein (UBL) SUMO have established roles in regulating the cellular response to DNA double-strand breaks (DSBs). A role for other UBLs, such as NEDD8, is also now emerging. This article provides an overview of the DDR, discusses our current understanding of the process and function of PTM by ubiquitin and NEDD8, and reviews the literature surrounding the role of ubiquitylation and neddylation in DNA repair processes, focusing particularly on DNA DSB repair.

scholarly journals In Vitro Nephrotoxicity Studies of Established and Experimental Platinum-Based Compounds

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1033
Author(s):  
Sarah Schoch ◽  
Vasily Sen ◽  
Walburgis Brenner ◽  
Andrea Hartwig ◽  
Beate Köberle
Keyword(s):  
Dna Damage ◽  
Proximal Tubule ◽  
Dna Damage Response ◽  
Transcriptional Response ◽  
Human Kidney ◽  
Epithelial Cell Line ◽  
Response Factors ◽  
Damage Response ◽  
Platinum Accumulation

Cisplatin is one of the most commonly used drugs for the treatment of various solid cancers. However, its efficacy is restricted by severe side effects, especially dose-limiting nephrotoxicity. New platinum-based compounds are designed to overcome this limitation. Previous investigations showed that the platinum(IV)–nitroxyl complex PN149 is highly cytotoxic in various tumor cell lines. In the present study, investigations with PN149 were extended to normal human kidney tubule epithelia. Coincident with higher intracellular platinum accumulation, the cytotoxicity of PN149 in the proximal tubule epithelial cell line ciPTEC was more pronounced compared to the established platinum chemotherapeutics cisplatin, carboplatin and oxaliplatin. Quantitative gene expression profiling revealed the induction of ROS-inducible and anti-oxidative genes, suggesting an oxidative stress response by PN149. However, in contrast to cisplatin, no pro-inflammatory response was observed. Genes coding for distinct DNA damage response factors and genes related to apoptosis were up-regulated, indicating the activation of the DNA damage response system and induction of the apoptotic cascade by PN149. Altogether, a comparable transcriptional response was observed for PN149 and the platinum chemotherapeutics. However, the lack of inflammatory activity, which is a possible cause contributing to toxicity in human renal proximal tubule epithelia, might indicate the reduced nephrotoxic potential of PN149.

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