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Aquatic Toxicology (Amsterdam,... Jun 2013The knowledge of DNA repair in a target species is of first importance as it is the primary line of defense against genotoxicants, and a better knowledge of DNA repair... (Review)
Review
The knowledge of DNA repair in a target species is of first importance as it is the primary line of defense against genotoxicants, and a better knowledge of DNA repair capacity in fish could help to interpret genotoxicity data and/or assist in the choice of target species, developmental stage and tissues to focus on, both for environmental biomonitoring studies and DNA repair testing. This review focuses in a first part on what is presently known on a mechanistic basis, about the various DNA repair systems in fish, in vivo and in established cell lines. Data on base excision repair (BER), direct reversal with O⁶-alkylguanine transferase and double strand breaks repair, although rather scarce, are being reviewed, as well as nucleotide excision repair (NER) and photoreactivation repair (PER), which are by far the most studied repair mechanisms in fish. Most of these repair mechanisms seem to be strongly species and tissue dependent; they also depend on the developmental stage of the organisms. BER is efficient in vivo, although no data has been found on in vitro models. NER activity is quite low or even inexistent depending on the studies; however this lack is partly compensated by a strong PER activity, especially in early developmental stage. In a second part, a survey of the ecotoxicological studies integrating DNA repair as a parameter responding to single or mixture of contaminant is realized. Three main approaches are being used: the measurement of DNA repair gene expression after exposure, although it has not yet been clearly established whether gene expression is indicative of repair capacity; the monitoring of DNA damage removal by following DNA repair kinetics; and the modulation of DNA repair activity following exposure in situ, in order to assess the impact of exposure history on DNA repair capacity. Since all DNA repair processes are possible targets for environmental pollutants, we can also wonder at which extent such a modulation of repair capacities in fish could be the base for the development of new biomarkers of genotoxicity. Knowing the importance of the germ cell DNA integrity in the reproductive success of aquatic organisms, the DNA repair capacity of such cells deserve to be more studied, as well as DNA repair capacities of established fish cell lines. The limited amount of available data, which shows low/slow DNA repair capacities of fish cell lines compared with mammalian cell lines, concerned mainly the NER system; thus this point merits to be explored more deeply. Additionally, since some of the DNA repair systems appear more efficient in embryo larval stages, it would be of interest to consider embryonic cell lineages more closely.
Topics: Animals; DNA Damage; DNA Repair; Ecotoxicology; Fishes; Germ Cells; Species Specificity
PubMed: 23571068
DOI: 10.1016/j.aquatox.2013.03.005 -
ACS Chemical Biology Oct 2017In 2011, Varela et al. reported that the PBRM1 gene is mutated in approximately 40% of clear cell renal cell carcinoma cases. Since then, the number of studies relating... (Review)
Review
In 2011, Varela et al. reported that the PBRM1 gene is mutated in approximately 40% of clear cell renal cell carcinoma cases. Since then, the number of studies relating PBRM1 mutations to cancers has substantially increased. BAF180 has now been linked to more than 30 types of cancers, including ccRCC, cholangiocarcinomas, esophageal squamous cell carcinoma, bladder cancer, and breast cancer. The mutations associated with BAF180 are most often truncations, which result in a loss of protein expression. This loss has been shown to adversely affect the expression of genes, likely because BAF180 is the chromatin recognition subunit of PBAF. In addition, BAF180 functions in numerous DNA repair mechanisms. Its roles in mediating DNA repair are likely the mechanism by which BAF180 acts a tumor suppressor protein. As research on this protein gains more interest, scientists will begin to piece together the complicated puzzle of the BAF180 protein and why its loss often results in cancer.
Topics: DNA Repair; DNA-Binding Proteins; Gene Expression Regulation; Humans; Mutation; Neoplasms; Nuclear Proteins; Transcription Factors
PubMed: 28921948
DOI: 10.1021/acschembio.7b00541 -
International Journal of Molecular... Sep 2020Precise gene editing is-or will soon be-in clinical use for several diseases, and more applications are under development. The programmable nuclease Cas9, directed by a... (Review)
Review
Precise gene editing is-or will soon be-in clinical use for several diseases, and more applications are under development. The programmable nuclease Cas9, directed by a single-guide RNA (sgRNA), can introduce double-strand breaks (DSBs) in target sites of genomic DNA, which constitutes the initial step of gene editing using this novel technology. In mammals, two pathways dominate the repair of the DSBs-nonhomologous end joining (NHEJ) and homology-directed repair (HDR)-and the outcome of gene editing mainly depends on the choice between these two repair pathways. Although HDR is attractive for its high fidelity, the choice of repair pathway is biased in a biological context. Mammalian cells preferentially employ NHEJ over HDR through several mechanisms: NHEJ is active throughout the cell cycle, whereas HDR is restricted to S/G2 phases; NHEJ is faster than HDR; and NHEJ suppresses the HDR process. This suggests that definitive control of outcome of the programmed DNA lesioning could be achieved through manipulating the choice of cellular repair pathway. In this review, we summarize the DSB repair pathways, the mechanisms involved in choice selection based on DNA resection, and make progress in the research investigating strategies that favor Cas9-mediated HDR based on the manipulation of repair pathway choice to increase the frequency of HDR in mammalian cells. The remaining problems in improving HDR efficiency are also discussed. This review should facilitate the development of CRISPR/Cas9 technology to achieve more precise gene editing.
Topics: Animals; CRISPR-Cas Systems; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Endonucleases; Gene Editing; Humans; RNA, Guide, CRISPR-Cas Systems; Recombinational DNA Repair
PubMed: 32899704
DOI: 10.3390/ijms21186461 -
Nature Reviews. Molecular Cell Biology Jul 2014Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise 'cut and patch'-type reaction. The global genome NER (GG-NER)... (Review)
Review
Nucleotide excision repair (NER) eliminates various structurally unrelated DNA lesions by a multiwise 'cut and patch'-type reaction. The global genome NER (GG-NER) subpathway prevents mutagenesis by probing the genome for helix-distorting lesions, whereas transcription-coupled NER (TC-NER) removes transcription-blocking lesions to permit unperturbed gene expression, thereby preventing cell death. Consequently, defects in GG-NER result in cancer predisposition, whereas defects in TC-NER cause a variety of diseases ranging from ultraviolet radiation-sensitive syndrome to severe premature ageing conditions such as Cockayne syndrome. Recent studies have uncovered new aspects of DNA-damage detection by NER, how NER is regulated by extensive post-translational modifications, and the dynamic chromatin interactions that control its efficiency. Based on these findings, a mechanistic model is proposed that explains the complex genotype-phenotype correlations of transcription-coupled repair disorders.
Topics: Aging; DNA Damage; DNA Repair; Humans; Models, Biological; Neoplasms; Ubiquitin
PubMed: 24954209
DOI: 10.1038/nrm3822 -
Cell Reports Mar 2022BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but...
BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but the exact mechanism of how BMI-1 participates in the process is unclear. Here, we establish a role for BMI-1 in the repair of DNA double-strand breaks by homologous recombination (HR), where it promotes DNA end resection. Mechanistically, BMI-1 mediates DNA end resection by facilitating the recruitment of CtIP, thus allowing RPA and RAD51 accumulation at DNA damage sites. Interestingly, treatment with transcription inhibitors rescues the DNA end resection defects of BMI-1-depleted cells, suggesting BMI-1-dependent transcriptional silencing mediates DNA end resection. Moreover, we find that H2A ubiquitylation at K119 (H2AK119ub) promotes end resection. Taken together, our results identify BMI-1-mediated transcriptional silencing and promotion of H2AK119ub deposition as essential regulators of DNA end resection and thus the progression of HR.
Topics: Body Mass Index; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Endodeoxyribonucleases; Homologous Recombination; Recombinational DNA Repair
PubMed: 35320715
DOI: 10.1016/j.celrep.2022.110536 -
International Journal of Molecular... Oct 2022Microhomology-mediated end joining (MMEJ) is a highly mutagenic pathway to repair double-strand breaks (DSBs). MMEJ was thought to be a backup pathway of homologous... (Review)
Review
Microhomology-mediated end joining (MMEJ) is a highly mutagenic pathway to repair double-strand breaks (DSBs). MMEJ was thought to be a backup pathway of homologous recombination (HR) and canonical nonhomologous end joining (C-NHEJ). However, it attracts more attention in cancer research due to its special function of microhomology in many different aspects of cancer. In particular, it is initiated with DNA end resection and upregulated in homologous recombination-deficient cancers. In this review, I summarize the following: (1) the recent findings and contributions of MMEJ to genome instability, including phenotypes relevant to MMEJ; (2) the interaction between MMEJ and other DNA repair pathways; (3) the proposed mechanistic model of MMEJ in DNA DSB repair and a new connection with microhomology-mediated break-induced replication (MMBIR); and (4) the potential clinical application by targeting MMEJ based on synthetic lethality for cancer therapy.
Topics: Humans; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Homologous Recombination; Genomic Instability; DNA
PubMed: 36361724
DOI: 10.3390/ijms232112937 -
Cancer Radiotherapie : Journal de La... Dec 2019Radiotherapy is one of the most common form of treatment in oncology care. Indeed, radiotherapy proved to be very effective in treating a wide range of malignancies....
Radiotherapy is one of the most common form of treatment in oncology care. Indeed, radiotherapy proved to be very effective in treating a wide range of malignancies. Nevertheless, certain tumours are intrinsically radioresistant or may evolve to become radioresistant. Resistance to radiotherapy is often associated with dysregulated DNA damage response and repair. Recently, a number of strategies have been developed to improve radiotherapy efficacy by targeting the DNA damage response and repair pathways. Ongoing clinical trials showed the potential of some of these approaches in enhancing radiotherapy, but also highlighted the possible limitations. Here, we will describe (i) the main mechanisms involved in double-strand break repair; (ii) available strategies that target these DNA repair processes to improve radiotherapy and (iii) the clinical outcomes and challenges that have emerged so far.
Topics: DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Humans; Neoplasms; Protein Kinase Inhibitors; Radiation Tolerance; Recombinational DNA Repair; Signal Transduction
PubMed: 31615730
DOI: 10.1016/j.canrad.2019.08.008 -
Cell Biology and Toxicology Oct 2018Maintenance of genome integrity is essential for all organisms because genome information regulates cell proliferation, growth arrest, and vital metabolic processes in... (Review)
Review
Maintenance of genome integrity is essential for all organisms because genome information regulates cell proliferation, growth arrest, and vital metabolic processes in cells, tissues, organs, and organisms. Because genomes are constantly exposed to intrinsic and extrinsic genotoxic stress, cellular DNA repair machinery and proper DNA damage responses (DDR) have evolved to quickly eliminate genotoxic DNA lesions, thus maintaining the genome integrity suitably. In human, germline mutations in genes involved not only in cellular DNA repair pathways but also in cellular DDR machinery frequently predispose hereditary diseases associated with chromosome aberrations. These genetic syndromes typically displaying mutations in DNA repair/DDR-related genes are often called "genome instability syndromes." Common features of these hereditary syndromes include a high incidence of cancers and developmental abnormalities including short stature, microcephaly, and/or neurological deficiencies. However, precisely how impaired DNA repair and/or dysfunctional DDR pathologically promote(s) these syndromes are poorly understood. In this review article, we summarize the clinical symptoms of several representatives "genome instability syndromes" and propose the plausible pathogenesis thereof.
Topics: DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Disease; Genomic Instability; Humans; Syndrome
PubMed: 29623483
DOI: 10.1007/s10565-018-9429-x -
Clinical Cancer Research : An Official... Sep 2010
Topics: Antineoplastic Agents; DNA Repair; Humans; Molecular Targeted Therapy; Neoplasms; Therapies, Investigational
PubMed: 20823139
DOI: 10.1158/1078-0432.CCR-10-2086 -
Cancer Treatment Reviews Nov 2009Increased chemo-resistance and radio-resistance of cancer cells is a major obstacle in the treatment and management of malignant cancers. An important mechanism that... (Review)
Review
Increased chemo-resistance and radio-resistance of cancer cells is a major obstacle in the treatment and management of malignant cancers. An important mechanism that underlies the development of such therapeutic resistance is that cancer cells recognize DNA lesions induced by DNA-damaging agents and by ionizing radiation, and repair these lesions by activating various DNA repair pathways. Therefore, Use of pharmacological agents that can inhibit certain DNA repair pathways in cancer cells has the potential for enhancing the targeted cytotoxicity of anticancer treatments and reversing the associated therapeutic resistance associated with DNA repair; such agents, offering a promising opportunity to achieve better therapeutic efficacy. Here we review the major DNA repair pathways and discuss recent advances in the development of novel inhibitors of DNA repair pathways; many of these agents are under preclinical/clinical investigation.
Topics: DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Humans; Neoplasms
PubMed: 19635647
DOI: 10.1016/j.ctrv.2009.06.005