scholarly journals Central Role of Ubiquitination in Genome Maintenance: DNA Replication and Damage Repair

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Soma Ghosh ◽  
Tapas Saha
Keyword(s):  
Dna Repair ◽  
Posttranslational Modifications ◽  
Excision Repair ◽  
Genetic Alterations ◽  
Conjugation System ◽  
Protein Ubiquitination ◽  
Independent Functions ◽  
Repair Mechanisms ◽  
Repair Pathways

Faithful transmission of genetic information through generations ensures genomic stability and integrity. However, genetic alterations occur every now and then during the course of genome duplication. In order to repair these genetic defects and lesions, nature has devised several repair pathways which function promptly to prevent the cell from accumulating permanent mutations. These repair mechanisms seem to be significantly impacted by posttranslational modifications of proteins like phosphorylation and ubiquitination. Protein ubiquitination is emerging as a critical regulatory mechanism of DNA damage response. Non-proteolytic, proteasome-independent functions of ubiquitin involving monoubiquitination and polyubiquitination of DNA repair proteins contribute significantly to the signaling of DNA repair pathways. In this paper, we will particularly highlight the work on ubiquitin-mediated signaling in the repair processes involving the Fanconi anemia pathway, translesional synthesis, nucleotide excision repair, and repair of double-strand breaks. We will also discuss the role of ubiquitin ligases in regulating checkpoint mechanisms, the role of deubiquitinating enzymes, and the growing possibilities of therapeutic intervention in this ubiquitin-conjugation system.

scholarly journals Molecular Mechanisms of the Whole DNA Repair System: A Comparison of Bacterial and Eukaryotic Systems

2010 ◽  
Vol 2010 ◽  
pp. 1-32 ◽  
Author(s):  
Rihito Morita ◽  
Shuhei Nakane ◽  
Atsuhiro Shimada ◽  
Masao Inoue ◽  
Hitoshi Iino ◽  
...  
Keyword(s):  
Dna Repair ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Thermus Thermophilus ◽  
Repair System ◽  
System A ◽  
Recombination Repair ◽  
Repair Mechanisms ◽  
Repair Pathways ◽  
Base Excision

DNA is subjected to many endogenous and exogenous damages. All organisms have developed a complex network of DNA repair mechanisms. A variety of different DNA repair pathways have been reported: direct reversal, base excision repair, nucleotide excision repair, mismatch repair, and recombination repair pathways. Recent studies of the fundamental mechanisms for DNA repair processes have revealed a complexity beyond that initially expected, with inter- and intrapathway complementation as well as functional interactions between proteins involved in repair pathways. In this paper we give a broad overview of the whole DNA repair system and focus on the molecular basis of the repair machineries, particularly inThermus thermophilusHB8.

scholarly journals Contribution of Base Excision Repair, Nucleotide Excision Repair, and DNA Recombination to Alkylation Resistance of the Fission Yeast Schizosaccharomyces pombe

2000 ◽  
Vol 182 (8) ◽  
pp. 2104-2112 ◽  
Author(s):  
Asli Memisoglu ◽  
Leona Samson
Keyword(s):  
Dna Repair ◽  
Schizosaccharomyces Pombe ◽  
Nucleotide Excision Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Recombination ◽  
Nucleotide Excision ◽  
Repair Pathways ◽  
Base Excision

ABSTRACT DNA damage is unavoidable, and organisms across the evolutionary spectrum possess DNA repair pathways that are critical for cell viability and genomic stability. To understand the role of base excision repair (BER) in protecting eukaryotic cells against alkylating agents, we generated Schizosaccharomyces pombe strains mutant for the mag1 3-methyladenine DNA glycosylase gene. We report that S. pombe mag1 mutants have only a slightly increased sensitivity to methylation damage, suggesting that Mag1-initiated BER plays a surprisingly minor role in alkylation resistance in this organism. We go on to show that other DNA repair pathways play a larger role than BER in alkylation resistance. Mutations in genes involved in nucleotide excision repair (rad13) and recombinational repair (rhp51) are much more alkylation sensitive thanmag1 mutants. In addition, S. pombe mutant for the flap endonuclease rad2 gene, whose precise function in DNA repair is unclear, were also more alkylation sensitive thanmag1 mutants. Further, mag1 andrad13 interact synergistically for alkylation resistance, and mag1 and rhp51 display a surprisingly complex genetic interaction. A model for the role of BER in the generation of alkylation-induced DNA strand breaks in S. pombe is discussed.

The role of DNA damage in laminopathy progeroid syndromes

2011 ◽  
Vol 39 (6) ◽  
pp. 1715-1718 ◽  
Author(s):  
Christopher J. Hutchison
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Therapeutic Approaches ◽  
Strand Breaks ◽  
Progeroid Syndromes ◽  
Repair Pathways

Progeroid laminopathies are characterized by the abnormal processing of lamin A, the appearance of misshapen nuclei, and the accumulation and persistence of DNA damage. In the present article, I consider the contribution of defective DNA damage pathways to the pathology of progeroid laminopathies. Defects in DNA repair pathways appear to be caused by a combination of factors. These include abnormal epigenetic modifications of chromatin that are required to recruit DNA repair pathways to sites of DNA damage, abnormal recruitment of DNA excision repair proteins to sites of DNA double-strand breaks, and unrepairable ROS (reactive oxygen species)-induced DNA damage. At least two of these defective processes offer the potential for novel therapeutic approaches.

AML1-ETO Inhibits DNA Repair Pathways and Promotes the Accumulation of DNA Damage and the Activation of p53.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1412-1412
Author(s):  
Ondrej Krejci ◽  
Mark Wunderlich ◽  
Junping Wei ◽  
Paul R. Andreassen ◽  
Thomas X. Lu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Gamma Irradiation ◽  
Malignant Transformation ◽  
Target Genes ◽  
Excision Repair ◽  
Genetic Alterations ◽  
P53 Pathway ◽  
Genetic Changes ◽  
Repair Pathways

Abstract Malignant transformation is a multistep process that is promoted by the accumulation of genetic changes over time. The contribution of individual genetic changes to the development of leukemia and the processes that induce these changes are not yet fully understood. The generation of the fusion gene AML1-ETO is thought to be an early event in the development of AML with t(8;21). Cells expressing AML1-ETO have been detected in samples from healthy newborns, as well as in patient samples analyzed long before the manifestation of AML. For these reasons it is assumed that a pre-leukemic clone expressing AML1-ETO requires additional genetic changes to complete the malignant transformation. However, the mechanism whereby these changes are acquired and the role that AML1-ETO plays in this process remain unclear. We used a model of human CD34+ cells expressing the AML1-ETO fusion protein to elucidate the role of AML1-ETO in leukemogenesis. AML1-ETO expressing (AE) cells displayed characteristics of a pre-leukemia, with enhanced self-renewal and NOD/SCID engraftment but no ability to induce malignancy in vivo. Analysis of gene expression using Affymetrix HG U133 Plus2.0 gene chips revealed that multiple genes important in various DNA repair pathways were suppressed in AE cells: OGG1, UNG, TDG, MBD4, POLB, POLE and FEN1 (Base Excision Repair), MRE11, RAD50, ATM, CHEK1 and CDC25A (ATM pathway), and FANCA, FANCL and BRCA2 (Fanconi anemia proteins). Treatment with DNA interstrand crosslinking agents mitomycin C or melphalan revealed a block in the S-phase of the cell cycle in AE cells at doses not affecting control cells. AE cells were also more sensitive to gamma irradiation compared to vector-transduced cells. In AE cultures, a gradual accumulation of cells with DNA damage was detected by immunofluorescence microscopy, using phosphorylated histone H2A.X as a marker. AE cells had a hyperactive p53 pathway with increased p53 protein levels, upregulation of its target genes (p21, TP53I3 and DAPK1), and increased apoptosis compared to control cultures, as might be expected in cells with chronic DNA damage. Incubation under low oxygen conditions prevented the accumulation of DNA damage and resulted in decreased expression of p53 target genes (TP53I3 and DAPK1), indicating that a sub-optimal response to the high oxygen stress of culture could be responsible for the accumulation of DNA damage foci and activation of the p53 pathway in AE cultures. Inhibition of p53 by shRNA led to increased resistance of AE cells to gamma irradiation but with continued high levels of DNA damage as shown by phosphorylated H2A.X. Interestingly, the POU4f1 transcription factor, a modifier of the p53 response pathway, has been found to be overexpressed in t(8;21) patient samples. In our system, AE cells that ectopically overexpressed POU4f1 following retroviral transduction showed decreased levels of p53 compared to vector-transduced AE cells. Inhibition of the p53 pathway in pre-leukemic clones expressing AML1-ETO could lead to a proliferative or survival advantage during periods of genotoxic stress. The impairment of DNA repair pathways and the accumulation of DNA damage in AML1-ETO-expressing cells may promote an elevated mutation rate and increase the chances of acquiring subsequent genetic alterations.

scholarly journals Fludarabine increases oxaliplatin cytotoxicity in normal and chronic lymphocytic leukemia lymphocytes by suppressing interstrand DNA crosslink removal

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4187-4193 ◽  
Author(s):  
Mazin A. Moufarij ◽  
Deepa Sampath ◽  
Michael J. Keating ◽  
William Plunkett
Keyword(s):  
Dna Repair ◽  
Chronic Lymphocytic Leukemia ◽  
Excision Repair ◽  
Mechanisms Of Action ◽  
Lymphocytic Leukemia ◽  
Dna Excision Repair ◽  
Interstrand Crosslinks ◽  
Repair Pathways ◽  
Major Target

Abstract Oxaliplatin and fludarabine have different but potentially complementary mechanisms of action. Previous studies have shown that DNA repair is a major target for fludarabine. We postulate that potentiation of oxaliplatin toxicity by fludarabine may be due to the inhibition by fludarabine of the activity of the DNA excision repair pathways activated by oxaliplatin adducts. To test this, we investigated the cytotoxic interactions between the 2 drugs in normal and chronic lymphocytic leukemia (CLL) lymphocytes. In each population, the combination resulted in greater than additive killing. Analysis of oxaliplatin damage revealed that fludarabine enhanced accumulation of interstrand crosslinks (ICLs) in specific regions of the genome in both populations, but to a lesser extent in normal lymphocytes. The action of fludarabine on the removal of oxaliplatin ICLs was explored to investigate the mechanism by which oxaliplatin toxicity was increased by fludarabine. Lymphocytes from patients with CLL have a greater capacity for ICL unhooking compared with normal lymphocytes. In the presence of fludarabine the extent of repair was significantly reduced in both populations, more so in CLL. Our findings support a role of fludarabine-mediated DNA repair inhibition as a mechanism critical for the cytotoxic synergy of the 2 drugs.

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 The Role of Posttranslational Modifications in DNA Repair

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Miaomiao Bai ◽  
Dongdong Ti ◽  
Qian Mei ◽  
Jiejie Liu ◽  
Xin Yan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein Interactions ◽  
Posttranslational Modifications ◽  
Genome Stability ◽  
Protein Localization ◽  
Complex Structure ◽  
Protein Protein Interactions ◽  
Regulate Protein

The human body is a complex structure of cells, which are exposed to many types of stress. Cells must utilize various mechanisms to protect their DNA from damage caused by metabolic and external sources to maintain genomic integrity and homeostasis and to prevent the development of cancer. DNA damage inevitably occurs regardless of physiological or abnormal conditions. In response to DNA damage, signaling pathways are activated to repair the damaged DNA or to induce cell apoptosis. During the process, posttranslational modifications (PTMs) can be used to modulate enzymatic activities and regulate protein stability, protein localization, and protein-protein interactions. Thus, PTMs in DNA repair should be studied. In this review, we will focus on the current understanding of the phosphorylation, poly(ADP-ribosyl)ation, ubiquitination, SUMOylation, acetylation, and methylation of six typical PTMs and summarize PTMs of the key proteins in DNA repair, providing important insight into the role of PTMs in the maintenance of genome stability and contributing to reveal new and selective therapeutic approaches to target cancers.

scholarly journals Systematic analysis of mutational spectra associated with DNA repair deficiency in C. elegans

2020 ◽  
Author(s):  
B Meier ◽  
NV Volkova ◽  
Y Hong ◽  
S Bertolini ◽  
V González-Huici ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Structural Variants ◽  
Systematic Analysis ◽  
C Elegans ◽  
Mutational Spectra ◽  
Base Substitutions ◽  
Repair Pathways ◽  
Complex Structural

AbstractGenome integrity is particularly important in germ cells to faithfully preserve genetic information across generations. As yet little is known about the contribution of various DNA repair pathways to prevent mutagenesis. Using the C. elegans model we analyse mutational spectra that arise in wild-type and 61 DNA repair and DNA damage response mutants cultivated over multiple generations. Overall, 44% of lines show >2-fold increased mutagenesis with a broad spectrum of mutational outcomes including changes in single or multiple types of base substitutions induced by defects in base excision or nucleotide excision repair, or elevated levels of 50-400 bp deletions in translesion polymerase mutants rev-3(pol ζ) and polh-1(pol η). Mutational signatures associated with defective homologous recombination fall into two classes: 1) mutants lacking brc-1/BRCA1 or rad-51/RAD51 paralogs show elevated base substitutions, indels and structural variants, while 2) deficiency for MUS-81/MUS81 and SLX-1/SLX1 nucleases, and HIM-6/BLM, HELQ-1/HELQ and RTEL-1/RTEL1 helicases primarily cause structural variants. Genome-wide investigation of mutagenesis patterns identified elevated rates of tandem duplications often associated with inverted repeats in helq-1 mutants, and a unique pattern of ‘translocation’ events involving homeologous sequences in rip-1 paralog mutants. atm-1/ATM DNA damage checkpoint mutants harboured complex structural variants enriched in subtelomeric regions, and chromosome end-to-end fusions. Finally, while inactivation of the p53-like gene cep-1 did not affect mutagenesis, combined brc-1 cep-1 deficiency displayed increased, locally clustered mutagenesis. In summary, we provide a global view of how DNA repair pathways prevent germ cell mutagenesis.

scholarly journals Mutational signatures are jointly shaped by DNA damage and repair

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadezda V. Volkova ◽  
Bettina Meier ◽  
Víctor González-Huici ◽  
Simone Bertolini ◽  
Santiago Gonzalez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Point Mutations ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
C Elegans ◽  
Dna Repair Deficiency ◽  
Dna Alterations ◽  
Repair Pathways

AbstractCells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.

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