scholarly journals Repairing of N-mustard derivative BO-1055 induced DNA damage requires NER, HR, and MGMT-dependent DNA repair mechanisms

Oncotarget ◽  
2015 ◽  
Vol 6 (28) ◽  
pp. 25770-25783 ◽  
Author(s):  
Ching-Ying Kuo ◽  
Wen-Cheng Chou ◽  
Chin-Chung Wu ◽  
Teng-Song Wong ◽  
Rajesh Kakadiya ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms

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 Ancient Sturgeons Possess Effective DNA Repair Mechanisms: Influence of Model Genotoxicants on Embryo Development of Sterlet, Acipenser ruthenus

2020 ◽  
Vol 22 (1) ◽  
pp. 6
Author(s):  
Ievgeniia Gazo ◽  
Roman Franěk ◽  
Radek Šindelka ◽  
Ievgen Lebeda ◽  
Sahana Shivaramu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Repair ◽  
Embryo Development ◽  
Hatching Rate ◽  
Embryo Survival ◽  
Dna Repair Mechanisms ◽  
Acipenser Ruthenus ◽  
Repair Mechanisms ◽  
Sterlet Acipenser Ruthenus

DNA damage caused by exogenous or endogenous factors is a common challenge for developing fish embryos. DNA damage repair (DDR) pathways help organisms minimize adverse effects of DNA alterations. In terms of DNA repair mechanisms, sturgeons represent a particularly interesting model due to their exceptional genome plasticity. Sterlet (Acipenser ruthenus) is a relatively small species of sturgeon. The goal of this study was to assess the sensitivity of sterlet embryos to model genotoxicants (camptothecin, etoposide, and benzo[a]pyrene), and to assess DDR responses. We assessed the effects of genotoxicants on embryo survival, hatching rate, DNA fragmentation, gene expression, and phosphorylation of H2AX and ATM kinase. Exposure of sterlet embryos to 1 µM benzo[a]pyrene induced low levels of DNA damage accompanied by ATM phosphorylation and xpc gene expression. Conversely, 20 µM etoposide exposure induced DNA damage without activation of known DDR pathways. Effects of 10 nM camptothecin on embryo development were stage-specific, with early stages, before gastrulation, being most sensitive. Overall, this study provides foundational information for future investigation of sterlet DDR pathways.

Aging and oxidative stress alter DNA repair mechanisms in male germ cells of superoxide dismutase-1 null mice

2021 ◽  
Author(s):  
Paulina Nguyen-Powanda ◽  
Bernard Robaire
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Repair ◽  
Superoxide Dismutase ◽  
Germ Cells ◽  
Superoxide Dismutase 1 ◽  
Male Germ Cells ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
And Oxidative Stress

Abstract The efficiency of antioxidant defense system decreases with aging, thus resulting in high levels of reactive oxygen species (ROS) and DNA damage in spermatozoa. This damage can lead to genetic disorders in the offspring. There are limited studies investigating the effects of the total loss of antioxidants, such as superoxide dismutase-1 (SOD1), in male germ cells as they progress through spermatogenesis. In this study, we evaluated the effects of aging and removing SOD1 (in male germ cells of SOD1-null (Sod1−/−) mice) in order to determine the potential mechanism(s) of DNA damage in these cells. Immunohistochemical analysis showed an increase in lipid peroxidation and DNA damage in the germ cells of aged wild-type (WT) and Sod1−/− mice of all age. Immunostaining of OGG1, a marker of base excision repair (BER), increased in aged WT and young Sod1−/− mice. In contrast, immunostaining intensity of LIGIV and RAD51, markers of non-homologous end-joining (NHEJ) and homologous recombination (HR), respectively, decreased in aged and Sod1−/− mice. Gene expression analysis showed similar results with altered mRNA expression of these key DNA repair transcripts in pachytene spermatocytes and round spermatids of aged and Sod1−/− mice. Our study indicates that DNA repair pathway markers of BER, NHEJ, and HR are differentially regulated as a function of aging and oxidative stress in spermatocytes and spermatids, and aging enhances the repair response to increased oxidative DNA damage, whereas impairments in other DNA repair mechanisms may contribute to the increase in DNA damage caused by aging and the loss of SOD1.

scholarly journals Obesity, DNA Damage, and Development of Obesity-Related Diseases

2019 ◽  
Vol 20 (5) ◽  
pp. 1146 ◽  
Author(s):  
Marta Włodarczyk ◽  
Grażyna Nowicka
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Dietary Habits ◽  
Cell Metabolism ◽  
Cancer Cell Proliferation ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Risk Assessment And Prevention ◽  
And Migration

Obesity has been recognized to increase the risk of such diseases as cardiovascular diseases, diabetes, and cancer. It indicates that obesity can impact genome stability. Oxidative stress and inflammation, commonly occurring in obesity, can induce DNA damage and inhibit DNA repair mechanisms. Accumulation of DNA damage can lead to an enhanced mutation rate and can alter gene expression resulting in disturbances in cell metabolism. Obesity-associated DNA damage can promote cancer growth by favoring cancer cell proliferation and migration, and resistance to apoptosis. Estimation of the DNA damage and/or disturbances in DNA repair could be potentially useful in the risk assessment and prevention of obesity-associated metabolic disorders as well as cancers. DNA damage in people with obesity appears to be reversible and both weight loss and improvement of dietary habits and diet composition can affect genome stability.

scholarly journals DNA repair mechanisms and gametogenesis

Reproduction ◽  
2001 ◽  
pp. 31-39 ◽  
Author(s):  
WM Baarends ◽  
R van der Laan ◽  
JA Grootegoed
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Gene Knockout ◽  
Cell Cycle Checkpoint ◽  
Checkpoint Control ◽  
Chromatin Dynamics ◽  
Dna Mismatch ◽  
Dna Repair Mechanisms ◽  
Genes Encoding ◽  
Repair Mechanisms

In mammals, there is a complex and intriguing relationship between DNA repair and gametogenesis. DNA repair mechanisms are involved not only in the repair of different types of DNA damage in developing germline cells, but also take part in the meiotic recombination process. Furthermore, the DNA repair mechanisms should tolerate mutations occurring during gametogenesis, to a limited extent. In the present review, several gametogenic aspects of DNA mismatch repair, homologous recombination repair and postreplication repair are discussed. In addition, the role of DNA damage-induced cell cycle checkpoint control is considered briefly. It appears that many genes encoding proteins that take part in DNA repair mechanisms show enhanced or specialized expression during mammalian gametogenesis, and several gene knockout mouse models show male or female infertility. On the basis of such knowledge and models, future experiments may provide more information about the precise relationship between DNA repair, chromatin dynamics, and genomic stability versus instability during gametogenesis.

Compromised Nuclear Sirtuins Activity Sensitizes BRCA-Proficient multiple Myeloma Cells to DNA Damage Agents

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 723-723
Author(s):  
Michele Cea ◽  
Antonia Cagnetta ◽  
Aditya Munshi ◽  
Yu-Tzu Tai ◽  
Teru Hideshima ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Dna Repair ◽  
Cell Lines ◽  
Plasma Cells ◽  
Dsb Repair ◽  
Dna Repair Mechanisms ◽  
Dna Damaging Agents ◽  
Normal Plasma ◽  
Repair Mechanisms

Abstract Abstract 723 Background: Multiple myeloma (MM) is a clonal malignancy of plasma cells with hallmark genetic instability resulting in large-scale changes at diagnosis, as well as further evolution contributing to disease progression. Inhibition of DNA repair mechanisms leads to significant reduction in acquisition of new genetic changes and associated progression of MM. Mammalian sirtuins are class III NAD+-dependent deacetylases emerging as innovative proteins involved in multiple pathways, including genome maintenance. Methods: A panel of 18 MM cell lines, both sensitive and resistant to conventional and novel anti-MM therapies, was used in the study. The antitumor effect of a pan-sirtuins inhibitor, Nicotinamide (Nam), alone and combined with DNA-damaging agents, was investigated by CTG assay and Annexin-V/propidium iodide staining. Mechanistic studies were performed with thymidine incorporation, Western-blotting, lentivirus-mediated shRNAs and immunofluorescence assay. Analysis of DNA DSB repair was done using chromosomally integrated reporter constructs, followed by cytometer analysis. Results: We analyzed an Affymetrix GeneChip (GSE6477) array of patient MM cells (n=162) compared with normal plasma cells, and found that transcript levels of two nuclear sirtuins (SIRT6 and SIRT7) were significantly higher in monoclonal gammopathy of undetermined significance (MGUS), smoldering MM, active MM, and relapsed MM compared with normal plasma cells. Importantly, protein analysis confirmed increased nuclear levels of these deacetylases in MM cell lines, including those resistant to DNA-damaging agents (MM.1R, LR-5, Dox40), as well as in patient CD138+ MM cells compared to PBMCs from healthy donors. Next we evaluated the functional role of these Sirtuins in MM cells by using loss of function approaches with RNAi. SIRT6 and SIRT7 silencing by knockdown reduced MM cell proliferation compared with control scrambled cells, with only a modest induction of cytotoxicity. We also examined the effects of Nam on DNA-damage response signaling triggered by conventional anti-MM agents melphalan and doxorubicin. Nam treatment did not appreciably affect MM cell viability; however, pretreatment with Nam impaired DNA double-strand breaks (DSBs) repair as well as DNA repair mechanisms triggered by conventional DNA damaging agents, evidenced by γH2AX and RPA phosphorylation, respectively. Consistent with these findings, Nam-pretreated MM cells formed fewer RAD51 foci in response to Doxorubicin and Melphalan, thereby conferring sensitivity to these agents. Importantly, this sensitizing effect was also observed in MM cells resistant to doxorubicin (RPMI-Doxo40) or melphalan (LR5), indicating that Nam increases chemosensitivity in both drug-sensitive and –resistant MM cells. Similarly, lentivirus-mediated shRNA knockdown of SIRT-6 and −7 sensitized MM cells to melphalan and doxorubicin. Finally, both chemical and genetic approaches improved the efficiency of DNA DSB repair mechanisms (Homologous and non-Homologous end-joining Recombination) in MM cell lines containing chromosomally integrated green fluorescent protein-based reporter constructs. Ongoing in vivo experiments are assessing how the chemical susceptibility of SIRT6 and/or 7-deficient cells can be exploited therapeutically. Conclusion: Our study demonstrates a link between nuclear sirtuins and DNA instability in MM cells, providing the basis for incorporation of inhibitors of these SIRTs into innovative anti-MM therapeutic approaches. Disclosures: Munshi: Celgene: Consultancy; Millenium: Consultancy; Merck: Consultancy; Onyx: Consultancy.

scholarly journals An age-related increase in resistance to DNA damage-induced apoptotic cell death is associated with development of DNA repair mechanisms

2003 ◽  
Vol 84 (6) ◽  
pp. 1275-1287 ◽  
Author(s):  
Alejandro A. Romero ◽  
Stephane R. Gross ◽  
Ke-Yi Cheng ◽  
Noriko K. Goldsmith ◽  
Herbert M. Geller
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Dna Repair Mechanisms ◽  
Age Related ◽  
Repair Mechanisms ◽  
Related Increase

Post-translational modifications of lysine in DNA-damage repair

2012 ◽  
Vol 52 ◽  
pp. 93-111 ◽  
Author(s):  
Snehajyoti Chatterjee ◽  
Parijat Senapati ◽  
Tapas K. Kundu
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Post Translational Modifications ◽  
Dna Repair Mechanisms ◽  
The Past ◽  
Damage Repair ◽  
Lysine Residues ◽  
Repair Mechanisms ◽  
Genotoxic Insult

DNA damage in cells is often the result of constant genotoxic insult. Nevertheless, efficient DNA repair pathways are able to maintain genomic integrity. Over the past decade it has been revealed that it is not only kinase signalling pathways which play a central role in this process, but also the different post-translational modifications at lysine residues of histone (chromatin) and non-histone proteins. These lysine modifications include acetylation, methylation, ubiquitination and SUMOylation. Genomic instability is often the major cause of different diseases, especially cancer, where lysine modifications are altered and thereby have an impact on the various DNA repair mechanisms. This chapter will discuss the recent advances in our understanding of the role of different lysine modifications in DNA repair and its physiological consequences.

scholarly journals Targeting DNA Repair Pathways in Hematological Malignancies

2020 ◽  
Vol 21 (19) ◽  
pp. 7365
Author(s):  
Jehad F. Alhmoud ◽  
Ayman G. Mustafa ◽  
Mohammed Imad Malki
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Essential Role ◽  
Hematological Malignancies ◽  
Hematological Malignancy ◽  
Genomic Changes ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Repair Pathways ◽  
The Impact

DNA repair plays an essential role in protecting cells that are repeatedly exposed to endogenous or exogenous insults that can induce varying degrees of DNA damage. Any defect in DNA repair mechanisms results in multiple genomic changes that ultimately may result in mutation, tumor growth, and/or cell apoptosis. Furthermore, impaired repair mechanisms can also lead to genomic instability, which can initiate tumorigenesis and development of hematological malignancy. This review discusses recent findings and highlights the importance of DNA repair components and the impact of their aberrations on hematological malignancies.

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