scholarly journals Targeting the DNA Damage Response to Overcome Cancer Drug Resistance in Glioblastoma

2020 ◽  
Vol 21 (14) ◽  
pp. 4910 ◽  
Author(s):  
Alessandra Ferri ◽  
Venturina Stagni ◽  
Daniela Barilà
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Kinase Inhibitors ◽  
Cancer Drug ◽  
Special Focus ◽  
Dna Repair Mechanisms ◽  
Cancer Drug Resistance ◽  
Damage Response ◽  
Repair Mechanisms ◽  
Future Therapy

Glioblastoma multiforme (GBM) is a severe brain tumor whose ability to mutate and adapt to therapies is at the base for the extremely poor survival rate of patients. Despite multiple efforts to develop alternative forms of treatment, advances have been disappointing and GBM remains an arduous tumor to treat. One of the leading causes for its strong resistance is the innate upregulation of DNA repair mechanisms. Since standard therapy consists of a combinatory use of ionizing radiation and alkylating drugs, which both damage DNA, targeting the DNA damage response (DDR) is proving to be a beneficial strategy to sensitize tumor cells to treatment. In this review, we will discuss how recent progress in the availability of the DDR kinase inhibitors will be key for future therapy development. Further, we will examine the principal existing DDR inhibitors, with special focus on those currently in use for GBM clinical trials.

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.

Abstract 2119: DCLK1 regulates ATR-DNA damage response for KRAS mutant lung cancer drug resistance and stemness

2019 ◽  
Author(s):  
Courtney Houchen ◽  
Janani Panneerselvam ◽  
Priyanga Mohandoss ◽  
Nathaniel Weygant ◽  
Randal May ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Drug Resistance ◽  
Dna Damage Response ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Damage Response

scholarly journals Connections between the Cell Cycle and the DNA Damage Response in Plants

2021 ◽  
Vol 22 (17) ◽  
pp. 9558
Author(s):  
Naomie Gentric ◽  
Pascal Genschik ◽  
Sandra Noir
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Genotoxic Stress ◽  
Dna Lesions ◽  
Cell Cycle Regulators ◽  
Dna Repair Mechanisms ◽  
Cycle Arrest ◽  
Damage Response ◽  
Repair Mechanisms

Due to their sessile lifestyle, plants are especially exposed to various stresses, including genotoxic stress, which results in altered genome integrity. Upon the detection of DNA damage, distinct cellular responses lead to cell cycle arrest and the induction of DNA repair mechanisms. Interestingly, it has been shown that some cell cycle regulators are not only required for meristem activity and plant development but are also key to cope with the occurrence of DNA lesions. In this review, we first summarize some important regulatory steps of the plant cell cycle and present a brief overview of the DNA damage response (DDR) mechanisms. Then, the role played by some cell cycle regulators at the interface between the cell cycle and DNA damage responses is discussed more specifically.

Abstract 2119: DCLK1 regulates ATR-DNA damage response for KRAS mutant lung cancer drug resistance and stemness

2019 ◽  
Author(s):  
Courtney Houchen ◽  
Janani Panneerselvam ◽  
Priyanga Mohandoss ◽  
Nathaniel Weygant ◽  
Randal May ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Drug Resistance ◽  
Dna Damage Response ◽  
Cancer Drug ◽  
Cancer Drug Resistance ◽  
Damage Response

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 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 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.

Breaking the DNA Damage Response via Serine/Threonine Kinase Inhibitors to Improve Cancer Treatment

2019 ◽  
Vol 26 (8) ◽  
pp. 1425-1445 ◽  
Author(s):  
Wioletta Rozpędek ◽  
Dariusz Pytel ◽  
Alicja Nowak-Zduńczyk ◽  
Dawid Lewko ◽  
Radosław Wojtczak ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Cancer Treatment ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Kinase Inhibitors ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Anti Cancer ◽  
Damage Response

Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/ threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death. Interestingly, key components of DDR signaling networks may constitute an attractive target for anti-cancer therapy through two distinct potential approaches: as chemoand radiosensitizers to enhance the effectiveness of currently used genotoxic treatment or as single agents to exploit defects in DDR in cancer cells via synthetic lethal approach. Moreover, the newest data reported that serine/threonine protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is also closely associated with cancer development and progression. Thereby, utilization of small-molecule, serine/threonine kinase inhibitors may provide a novel, groundbreaking, anti-cancer treatment strategy. Currently, a range of potent, highlyselective toward ATM, ATR and PERK inhibitors has been discovered, but after foregoing study, additional investigations are necessary for their future clinical use.

scholarly journals Anti-cancer drug KP1019 modulates epigenetics and induces DNA damage response inSaccharomyces cerevisiae

FEBS Letters ◽  
2014 ◽  
Vol 588 (6) ◽  
pp. 1044-1052 ◽  
Author(s):  
Vikash Singh ◽  
Gajendra Kumar Azad ◽  
Papita Mandal ◽  
M. Amarendar Reddy ◽  
Raghuvir S. Tomar
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cancer Drug ◽  
Anti Cancer ◽  
Damage Response
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