Targeting DNA Repair Pathways in Hematological Malignancies

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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Archaeal DNA Repair Mechanisms

Biomolecules ◽

10.3390/biom10111472 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1472

Author(s):

Craig J. Marshall ◽

Thomas J. Santangelo

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Molecular Mechanisms ◽

Genomic Integrity ◽

Dna Stability ◽

Dna Repair Mechanisms ◽

Environmental Extremes ◽

Repair Mechanisms ◽

Repair Pathways ◽

Damage Types

Archaea often thrive in environmental extremes, enduring levels of heat, pressure, salinity, pH, and radiation that prove intolerable to most life. Many environmental extremes raise the propensity for DNA damaging events and thus, impact DNA stability, placing greater reliance on molecular mechanisms that recognize DNA damage and initiate accurate repair. Archaea can presumably prosper in harsh and DNA-damaging environments in part due to robust DNA repair pathways but surprisingly, no DNA repair pathways unique to Archaea have been described. Here, we review the most recent advances in our understanding of archaeal DNA repair. We summarize DNA damage types and their consequences, their recognition by host enzymes, and how the collective activities of many DNA repair pathways maintain archaeal genomic integrity.

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Formation and Recognition of UV-Induced DNA Damage within Genome Complexity

International Journal of Molecular Sciences ◽

10.3390/ijms21186689 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6689

Author(s):

Philippe Johann to Berens ◽

Jean Molinier

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Uv Light ◽

Dna Repair Mechanisms ◽

Genome Complexity ◽

Repair Mechanisms ◽

Living Organisms ◽

Genomic Regions ◽

The Impact

Ultraviolet (UV) light is a natural genotoxic agent leading to the formation of photolesions endangering the genomic integrity and thereby the survival of living organisms. To prevent the mutagenetic effect of UV, several specific DNA repair mechanisms are mobilized to accurately maintain genome integrity at photodamaged sites within the complexity of genome structures. However, a fundamental gap remains to be filled in the identification and characterization of factors at the nexus of UV-induced DNA damage, DNA repair, and epigenetics. This review brings together the impact of the epigenomic context on the susceptibility of genomic regions to form photodamage and focuses on the mechanisms of photolesions recognition through the different DNA repair pathways.

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DNA Damage and Its Cellular Response in Mother and Fetus Exposed to Hyperglycemic Environment

BioMed Research International ◽

10.1155/2014/676758 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 15

Author(s):

Jusciele Brogin Moreli ◽

Janine Hertzog Santos ◽

Clarissa Ribeiro Rocha ◽

Débora Cristina Damasceno ◽

Glilciane Morceli ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Dna Repair ◽

Cellular Response ◽

Genetic Material ◽

Endogenous Factors ◽

Dna Repair Mechanisms ◽

Scavenging Capacity ◽

Repair Mechanisms ◽

The Impact

The increased production of reactive oxygen species (ROS) plays a key role in pathogenesis of diabetic complications. ROS are generated by exogenous and endogenous factors such as during hyperglycemia. When ROS production exceeds the detoxification and scavenging capacity of the cell, oxidative stress ensues. Oxidative stress induces DNA damage and when DNA damage exceeds the cellular capacity to repair it, the accumulation of errors can overwhelm the cell resulting in cell death or fixation of genome mutations that can be transmitted to future cell generations. These mutations can lead to and/or play a role in cancer development. This review aims at (i) understanding the types and consequences of DNA damage during hyperglycemic pregnancy; (ii) identifying the biological role of DNA repair during pregnancy, and (iii) proposing clinical interventions to maintain genome integrity. While hyperglycemia can damage the maternal genetic material, the impact of hyperglycemia on fetal cells is still unclear. DNA repair mechanisms may be important to prevent the deleterious effects of hyperglycemia both in mother and in fetus DNA and, as such, prevent the development of diseases in adulthood. Hence, in clinical practice, maternal glycemic control may represent an important point of intervention to prevent the deleterious effects of maternal hyperglycemia to DNA.

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

Cancers ◽

10.3390/cancers13030504 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22010006 ◽

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.

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

Biology of Reproduction ◽

10.1093/biolre/ioab114 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms20051146 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1146 ◽

Cited By ~ 30

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.

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DNA repair mechanisms and gametogenesis

Reproduction ◽

10.1530/rep.0.1210031 ◽

2001 ◽

pp. 31-39 ◽

Cited By ~ 105

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.

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