scholarly journals Take a Break to Repair: A Dip in the World of Double-Strand Break Repair Mechanisms Pointing the Gaze on Archaea

2021 ◽  
Vol 22 (24) ◽  
pp. 13296
Author(s):  
Mariarosaria De Falco ◽  
Mariarita De Felice
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Genome Stability ◽  
Developmental Disorders ◽  
Strand Break ◽  
Human Diseases ◽  
Dna Damages ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Repair Pathways

All organisms have evolved many DNA repair pathways to counteract the different types of DNA damages. The detection of DNA damage leads to distinct cellular responses that bring about cell cycle arrest and the induction of DNA repair mechanisms. In particular, DNA double-strand breaks (DSBs) are extremely toxic for cell survival, that is why cells use specific mechanisms of DNA repair in order to maintain genome stability. The choice among the repair pathways is mainly linked to the cell cycle phases. Indeed, if it occurs in an inappropriate cellular context, it may cause genome rearrangements, giving rise to many types of human diseases, from developmental disorders to cancer. Here, we analyze the most recent remarks about the main pathways of DSB repair with the focus on homologous recombination. A thorough knowledge in DNA repair mechanisms is pivotal for identifying the most accurate treatments in human diseases.

scholarly journals Activation of efficient DNA repair mechanisms after photon and proton irradiation of human chondrosarcoma cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Birgit Lohberger ◽  
Dietmar Glänzer ◽  
Nicole Eck ◽  
Sylvia Kerschbaum-Gruber ◽  
Elisabeth Mara ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Molecular Mechanisms ◽  
Proton Irradiation ◽  
Particle Therapy ◽  
Dna Damages ◽  
X Ray ◽  
Dna Repair Mechanisms ◽  
Key Players ◽  
Repair Mechanisms

AbstractAlthough particle therapy with protons has proven to be beneficial in the treatment of chondrosarcoma compared to photon-based (X-ray) radiation therapy, the cellular and molecular mechanisms have not yet been sufficiently investigated. Cell viability and colony forming ability were analyzed after X-ray and proton irradiation (IR). Cell cycle was analyzed using flow cytometry and corresponding regulator genes and key players of the DNA repair mechanisms were measured using next generation sequencing, protein expression and immunofluorescence staining. Changes in metabolic phenotypes were determined with nuclear magnetic resonance spectroscopy. Both X-ray and proton IR resulted in reduced cell survival and a G2/M phase arrest of the cell cycle. Especially 1 h after IR, a significant dose-dependent increase of phosphorylated γH2AX foci was observed. This was accompanied with a reprogramming in cellular metabolism. Interestingly, within 24 h the majority of clearly visible DNA damages were repaired and the metabolic phenotype restored. Involved DNA repair mechanisms are, besides the homology directed repair (HDR) and the non-homologous end-joining (NHEJ), especially the mismatch mediated repair (MMR) pathway with the key players EXO1, MSH3, and PCNA. Chondrosarcoma cells regenerates the majority of DNA damages within 24 h. These molecular mechanisms represent an important basis for an improved therapy.

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 Homologous Recombination Repair Polymorphisms and the Risk for Osteosarcoma / Polimorfizam Gena Odgovornih Za Reparaciju Dnk Homolognom Rekombinacijom I Rizikza Pojavu Osteosarkoma

2015 ◽  
Vol 34 (2) ◽  
pp. 200-206 ◽  
Author(s):  
Katja Goričar ◽  
Viljem Kovač ◽  
Janez Jazbec ◽  
Janez Lamovec ◽  
Vita Dolžan
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Cancer Susceptibility ◽  
Homologous Recombination Repair ◽  
Nucleotide Polymorphisms ◽  
Dna Repair Mechanisms ◽  
Recombination Repair ◽  
Repair Mechanisms ◽  
Repair Genes

Summary Background: DNA repair mechanisms are essential for maintaining genome stability, and genetic variability in DNA repair genes may contribute to cancer susceptibility. Our aim was to evaluate the influence of polymorphisms in the homologous recombination repair genes XRCC3, RAD51, and NBN on the risk for osteosarcoma. Methods: In total, 79 osteosarcoma cases and 373 controls were genotyped for eight single nucleotide polymorphisms (SNPs) in XRCC3, RAD51, and NBN. Logistic regression was used to determine the association of these SNPs with risk for osteosarcoma. Results: None of the investigated SNPs was associated with risk for osteosarcoma in the whole cohort of patients, however, in patients diagnosed before the age of thirty years XRCC3 rs861539 C>T and NBN rs1805794 G>C were associated with significantly decreased risk for osteosarcoma (P=0.047, OR=0.54, 95% CI=0.30-0.99 and P=0.036, OR=0.42, 95% CI=0.19-0.94, respectively). Moreover, in the carriers of a combination of polymorphic alleles in both SNPs risk for osteosarcoma was decreased even more significantly (Ptrend=0.007). The risk for developing osteosarcoma was the lowest in patients with no wild-type alleles for both SNPs (P=0.039, OR=0.31, 95% CI=0.10-0.94). Conclusions: Our results suggest that polymorphisms in homologous recombination repair genes might contribute to risk for osteosarcoma in patients diagnosed below the age of thirty years.

scholarly journals The roles of RNA in DNA double-strand break repair

2020 ◽  
Vol 122 (5) ◽  
pp. 613-623 ◽  
Author(s):  
Aldo S. Bader ◽  
Ben R. Hawley ◽  
Ania Wilczynska ◽  
Martin Bushell
Keyword(s):  
Dna Repair ◽  
Cancer Progression ◽  
Genome Stability ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Critical Role ◽  
Strand Break ◽  
Rna Molecules ◽  
Repair Mechanisms ◽  
Recent Developments

AbstractEffective DNA repair is essential for cell survival: a failure to correctly repair damage leads to the accumulation of mutations and is the driving force for carcinogenesis. Multiple pathways have evolved to protect against both intrinsic and extrinsic genotoxic events, and recent developments have highlighted an unforeseen critical role for RNA in ensuring genome stability. It is currently unclear exactly how RNA molecules participate in the repair pathways, although many models have been proposed and it is possible that RNA acts in diverse ways to facilitate DNA repair. A number of well-documented DNA repair factors have been described to have RNA-binding capacities and, moreover, screens investigating DNA-damage repair mechanisms have identified RNA-binding proteins as a major group of novel factors involved in DNA repair. In this review, we integrate some of these datasets to identify commonalities that might highlight novel and interesting factors for future investigations. This emerging role for RNA opens up a new dimension in the field of DNA repair; we discuss its impact on our current understanding of DNA repair processes and consider how it might influence cancer progression.

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.

scholarly journals Preserving genome integrity in human cells via DNA double-strand break repair

2020 ◽  
Vol 31 (9) ◽  
pp. 859-865 ◽  
Author(s):  
Ryan B. Jensen ◽  
Eli Rothenberg
Keyword(s):  
Dna Repair ◽  
Strand Break ◽  
Double Strand Break ◽  
Human Cells ◽  
Cell Cycle Checkpoints ◽  
Human Diseases ◽  
Genome Integrity ◽  
Dsb Repair ◽  
Dna Double Strand Break ◽  
Repair Pathways

The efficient maintenance of genome integrity in the face of cellular stress is vital to protect against human diseases such as cancer. DNA replication, chromatin dynamics, cellular signaling, nuclear architecture, cell cycle checkpoints, and other cellular activities contribute to the delicate spatiotemporal control that cells utilize to regulate and maintain genome stability. This perspective will highlight DNA double-strand break (DSB) repair pathways in human cells, how DNA repair failures can lead to human disease, and how PARP inhibitors have emerged as a novel clinical therapy to treat homologous recombination-deficient tumors. We briefly discuss how failures in DNA repair produce a permissive genetic environment in which preneoplastic cells evolve to reach their full tumorigenic potential. Finally, we conclude that an in-depth understanding of DNA DSB repair pathways in human cells will lead to novel therapeutic strategies to treat cancer and potentially other human diseases.

scholarly journals Tools for Decoding Ubiquitin Signaling in DNA Repair

2021 ◽  
Vol 9 ◽  
Author(s):  
Benjamin Foster ◽  
Martin Attwood ◽  
Ian Gibbs-Seymour
Keyword(s):  
Dna Repair ◽  
Mammalian Cells ◽  
Genome Stability ◽  
Dna Lesions ◽  
Post Translational Modifications ◽  
Dna Repair Mechanisms ◽  
Repair Processes ◽  
Repair Mechanisms ◽  
Mechanistic Basis ◽  
Cellular Dna

The maintenance of genome stability requires dedicated DNA repair processes and pathways that are essential for the faithful duplication and propagation of chromosomes. These DNA repair mechanisms counteract the potentially deleterious impact of the frequent genotoxic challenges faced by cells from both exogenous and endogenous agents. Intrinsic to these mechanisms, cells have an arsenal of protein factors that can be utilised to promote repair processes in response to DNA lesions. Orchestration of the protein factors within the various cellular DNA repair pathways is performed, in part, by post-translational modifications, such as phosphorylation, ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs). In this review, we firstly explore recent advances in the tools for identifying factors involved in both DNA repair and ubiquitin signaling pathways. We then expand on this by evaluating the growing repertoire of proteomic, biochemical and structural techniques available to further understand the mechanistic basis by which these complex modifications regulate DNA repair. Together, we provide a snapshot of the range of methods now available to investigate and decode how ubiquitin signaling can promote DNA repair and maintain genome stability in mammalian cells.

scholarly journals Evolution-based screening enables genome-wide prioritization and discovery of DNA repair genes

2019 ◽  
Vol 116 (39) ◽  
pp. 19593-19599 ◽  
Author(s):  
Gregory J. Brunette ◽  
Mohd A. Jamalruddin ◽  
Robert A. Baldock ◽  
Nathan L. Clark ◽  
Kara A. Bernstein
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Genome Stability ◽  
Strand Break ◽  
Evolutionary Analysis ◽  
Dna Double Strand Breaks ◽  
Atm Kinase ◽  
Functional Relationships ◽  
Genome Wide ◽  
Repair Pathways

DNA repair is critical for genome stability and is maintained through conserved pathways. Traditional genome-wide mammalian screens are both expensive and laborious. However, computational approaches circumvent these limitations and are a powerful tool to identify new DNA repair factors. By analyzing the evolutionary relationships between genes in the major DNA repair pathways, we uncovered functional relationships between individual genes and identified partners. Here we ranked 17,487 mammalian genes for coevolution with 6 distinct DNA repair pathways. Direct comparison to genetic screens for homologous recombination or Fanconi anemia factors indicates that our evolution-based screen is comparable, if not superior, to traditional screening approaches. Demonstrating the utility of our strategy, we identify a role for the DNA damage-induced apoptosis suppressor (DDIAS) gene in double-strand break repair based on its coevolution with homologous recombination. DDIAS knockdown results in DNA double-strand breaks, indicated by ATM kinase activation and 53BP1 foci induction. Additionally, DDIAS-depleted cells are deficient for homologous recombination. Our results reveal that evolutionary analysis is a powerful tool to uncover novel factors and functional relationships in DNA repair.

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