Nanoparticle-Encapsulated Camptothecin: Epigenetic Modulation in DNA Repair Mechanisms in Colon Cancer Cells

Molecular crosstalk between the cellular epigenome and genome converge as a synergistic driver of oncogenic transformations. Besides other pathways, epigenetic regulatory circuits exert their effect towards cancer progression through the induction of DNA repair deficiencies. We explored this mechanism using a camptothecin encapsulated in β-cyclodextrin–EDTA–Fe3O4 nanoparticles (CPT-CEF)-treated HT29 cells model. We previously demonstrated that CPT-CEF treatment of HT29 cells effectively induces apoptosis and cell cycle arrest, stalling cancer progression. A comparative transcriptome analysis of CPT-CEF-treated versus untreated HT29 cells indicated that genes controlling mismatch repair, base excision repair, and homologues recombination were downregulated in these cancer cells. Our study demonstrated that treatment with CPT-CEF alleviated this repression. We observed that CPT-CEF exerts its effect by possibly affecting the DNA repair mechanism through epigenetic modulation involving genes of HMGB1, APEX1, and POLE3. Hence, we propose that CPT-CEF could be a DNA repair modulator that harnesses the cell’s epigenomic plasticity to amend DNA repair deficiencies in cancer cells.

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

Journal of Nucleic Acids ◽

10.4061/2010/179594 ◽

2010 ◽

Vol 2010 ◽

pp. 1-32 ◽

Cited By ~ 45

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.

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Impact of hypoxia on DNA repair and genome integrity

Mutagenesis ◽

10.1093/mutage/gez019 ◽

2019 ◽

Vol 35 (1) ◽

pp. 61-68 ◽

Cited By ~ 5

Author(s):

Alanna R Kaplan ◽

Peter M Glazer

Keyword(s):

Dna Repair ◽

Cancer Progression ◽

Base Excision Repair ◽

Mutation Frequency ◽

Excision Repair ◽

Tumour Microenvironment ◽

Genome Integrity ◽

Future Directions ◽

Homology Directed Repair ◽

Base Excision

Abstract Hypoxia is a hallmark of the tumour microenvironment with profound effects on tumour biology, influencing cancer progression, the development of metastasis and patient outcome. Hypoxia also contributes to genomic instability and mutation frequency by inhibiting DNA repair pathways. This review summarises the diverse mechanisms by which hypoxia affects DNA repair, including suppression of homology-directed repair, mismatch repair and base excision repair. We also discuss the effects of hypoxia mimetics and agents that induce hypoxia on DNA repair, and we highlight areas of potential clinical relevance as well as future directions.

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Databases and Bioinformatics Tools for the Study of DNA Repair

Molecular Biology International ◽

10.4061/2011/475718 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Kaja Milanowska ◽

Kristian Rother ◽

Janusz M. Bujnicki

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Excision Repair ◽

Uv Light ◽

Dna Lesions ◽

Environmental Chemicals ◽

Nonhomologous End Joining ◽

End Joining ◽

Repair Mechanisms ◽

Base Excision

DNA is continuously exposed to many different damaging agents such as environmental chemicals, UV light, ionizing radiation, and reactive cellular metabolites. DNA lesions can result in different phenotypical consequences ranging from a number of diseases, including cancer, to cellular malfunction, cell death, or aging. To counteract the deleterious effects of DNA damage, cells have developed various repair systems, including biochemical pathways responsible for the removal of single-strand lesions such as base excision repair (BER) and nucleotide excision repair (NER) or specialized polymerases temporarily taking over lesion-arrested DNA polymerases during the S phase in translesion synthesis (TLS). There are also other mechanisms of DNA repair such as homologous recombination repair (HRR), nonhomologous end-joining repair (NHEJ), or DNA damage response system (DDR). This paper reviews bioinformatics resources specialized in disseminating information about DNA repair pathways, proteins involved in repair mechanisms, damaging agents, and DNA lesions.

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The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals

Biochemical Journal ◽

10.1042/bj20101116 ◽

2010 ◽

Vol 432 (1) ◽

pp. 165-172 ◽

Cited By ~ 22

Author(s):

René Thierbach ◽

Gunnar Drewes ◽

Markus Fusser ◽

Anja Voigt ◽

Doreen Kuhlow ◽

...

Keyword(s):

Dna Repair ◽

Neurodegenerative Disorder ◽

Excision Repair ◽

Friedreich’S Ataxia ◽

Friedreich's Ataxia ◽

Liver Tumours ◽

Dna Repair Mechanisms ◽

Dna Base ◽

Repair Mechanisms ◽

Base Excision

DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron–sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.

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HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1600485113 ◽

2016 ◽

Vol 113 (19) ◽

pp. 5311-5316 ◽

Cited By ~ 59

Author(s):

Hichem Lahouassa ◽

Marie-Lise Blondot ◽

Lise Chauveau ◽

Ghina Chougui ◽

Marina Morel ◽

...

Keyword(s):

Dna Repair ◽

Excision Repair ◽

Host Cells ◽

Uracil Dna Glycosylase ◽

Proteomic Screen ◽

Cycle Arrest ◽

Immunodeficiency Virus ◽

Base Excision ◽

Hiv 1 ◽

Dna Translocase

Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1–cullin4-associated-factor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.

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DNA repair-related genes in sugarcane expressed sequence tags (ESTs)

Genetics and Molecular Biology ◽

10.1590/s1415-47572001000100018 ◽

2001 ◽

Vol 24 (1-4) ◽

pp. 131-140 ◽

Cited By ~ 10

Author(s):

R.M.A. Costa ◽

W.C. Lima ◽

C.I.G. Vogel ◽

C.M. Berra ◽

D.D. Luche ◽

...

Keyword(s):

Dna Repair ◽

Expressed Sequence Tag ◽

Excision Repair ◽

Origin And Evolution ◽

Dna Repair Mechanisms ◽

Dna Lesion ◽

Repair Mechanisms ◽

Base Excision ◽

High Level ◽

Expressed Sequence

There is much interest in the identification and characterization of genes involved in DNA repair because of their importance in the maintenance of the genome integrity. The high level of conservation of DNA repair genes means that these genetic elements may be used in phylogenetic studies as a source of information on the genetic origin and evolution of species. The mechanisms by which damaged DNA is repaired are well understood in bacteria, yeast and mammals, but much remains to be learned as regards plants. We identified genes involved in DNA repair mechanisms in sugarcane using a similarity search of the Brazilian Sugarcane Expressed Sequence Tag (SUCEST) database against known sequences deposited in other public databases (National Center of Biotechnology Information (NCBI) database and the Munich Information Center for Protein Sequences (MIPS) Arabidopsis thaliana database). This search revealed that most of the various proteins involved in DNA repair in sugarcane are similar to those found in other eukaryotes. However, we also identified certain intriguing features found only in plants, probably due to the independent evolution of this kingdom. The DNA repair mechanisms investigated include photoreactivation, base excision repair, nucleotide excision repair, mismatch repair, non-homologous end joining, homologous recombination repair and DNA lesion tolerance. We report the main differences found in the DNA repair machinery in plant cells as compared to other organisms. These differences point to potentially different strategies plants employ to deal with DNA damage, that deserve further investigation.

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DNA Repair Pathways in Clinical Practice: Lessons From Pediatric Cancer Susceptibility Syndromes

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.4171 ◽

2006 ◽

Vol 24 (23) ◽

pp. 3799-3808 ◽

Cited By ~ 205

Author(s):

Richard D. Kennedy ◽

Alan D. D'Andrea

Keyword(s):

Dna Repair ◽

Cancer Cells ◽

Fanconi Anemia ◽

Drug Sensitivity ◽

Cancer Susceptibility ◽

Excision Repair ◽

Cancer Management ◽

Ovarian Epithelial Tumors ◽

Repair Pathways ◽

Base Excision

Human cancers exhibit genomic instability and an increased mutation rate due to underlying defects in DNA repair. Cancer cells are often defective in one of six major DNA repair pathways, namely: mismatch repair, base excision repair, nucleotide excision repair, homologous recombination, nonhomologous endjoining and translesion synthesis. The specific DNA repair pathway affected is predictive of the kinds of mutations, the tumor drug sensitivity, and the treatment outcome. The study of rare inherited DNA repair disorders, such as Fanconi anemia, has yielded new insights to drug sensitivity and treatment of sporadic cancers, such as breast or ovarian epithelial tumors, in the general population. The Fanconi anemia pathway is an example of how DNA repair pathways can be deregulated in cancer cells and how biomarkers of the integrity of these pathways could be useful as a guide to cancer management and may be used in the development of novel therapeutic agents.

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Oncometabolites and the response to radiotherapy

Radiation Oncology ◽

10.1186/s13014-020-01638-9 ◽

2020 ◽

Vol 15 (1) ◽

Cited By ~ 1

Author(s):

Kexu Xiang ◽

Verena Jendrossek ◽

Johann Matschke

Keyword(s):

Dna Repair ◽

Cancer Cells ◽

Cancer Patients ◽

Cancer Progression ◽

Multidisciplinary Treatment ◽

Metabolic Enzymes ◽

Therapeutic Effects ◽

Dna Double Strand Breaks ◽

Cellular Processes ◽

Epigenetic Modulation

AbstractRadiotherapy (RT) is applied in 45–60% of all cancer patients either alone or in multimodal therapy concepts comprising surgery, RT and chemotherapy. However, despite technical innovations approximately only 50% are cured, highlight a high medical need for innovation in RT practice. RT is a multidisciplinary treatment involving medicine and physics, but has always been successful in integrating emerging novel concepts from cancer and radiation biology for improving therapy outcome. Currently, substantial improvements are expected from integration of precision medicine approaches into RT concepts.Altered metabolism is an important feature of cancer cells and a driving force for malignant progression. Proper metabolic processes are essential to maintain and drive all energy-demanding cellular processes, e.g. repair of DNA double-strand breaks (DSBs). Consequently, metabolic bottlenecks might allow therapeutic intervention in cancer patients.Increasing evidence now indicates that oncogenic activation of metabolic enzymes, oncogenic activities of mutated metabolic enzymes, or adverse conditions in the tumor microenvironment can result in abnormal production of metabolites promoting cancer progression, e.g. 2-hyroxyglutarate (2-HG), succinate and fumarate, respectively. Interestingly, these so-called “oncometabolites” not only modulate cell signaling but also impact the response of cancer cells to chemotherapy and RT, presumably by epigenetic modulation of DNA repair.Here we aimed to introduce the biological basis of oncometabolite production and of their actions on epigenetic regulation of DNA repair. Furthermore, the review will highlight innovative therapeutic opportunities arising from the interaction of oncometabolites with DNA repair regulation for specifically enhancing the therapeutic effects of genotoxic treatments including RT in cancer patients.

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Beyond Base Excision Repair: An evolving picture of mitochondrial DNA repair

Bioscience Reports ◽

10.1042/bsr20211320 ◽

2021 ◽

Author(s):

Kathrin Allkanjari ◽

Robert A Baldock

Keyword(s):

Dna Repair ◽

Mitochondrial Dna ◽

Mitochondrial Genome ◽

Base Excision Repair ◽

Excision Repair ◽

Cellular Aging ◽

Cellular Respiration ◽

Dna Repair Proteins ◽

Repair Mechanisms ◽

Base Excision

Mitochondria are highly specialised organelles required for cellular processes including ATP-production through cellular respiration and controlling apoptosis. Mitochondria contain their own DNA genome which encodes both protein and RNA required for cellular respiration. Each cell may contain hundreds to thousands of copies of the mitochondrial genome, which is essential for normal cellular function – deviation of mitochondrial DNA (mtDNA) copy number is associated with cellular aging and disease. Furthermore, mtDNA lesions can arise from both endogenous or exogenous sources and must either be tolerated or corrected to preserve mitochondrial function. Importantly, replication of damaged mtDNA can lead to stalling and introduction of mutations or genetic loss, mitochondria have adapted mechanisms to repair damaged DNA. These mechanisms rely on nuclear encoded DNA repair proteins that are translocated into the mitochondria. Despite the presence of many known nuclear DNA repair proteins being found in the mitochondrial proteome, it remains to be established which DNA repair mechanisms are functional in mammalian mitochondria. Here, we summarise the existing and emerging research, alongside examining proteomic evidence, demonstrating that mtDNA damage can be repaired using Base Excision Repair (BER), Homologous Recombination (HR) and Microhomology-mediated End Joining (MMEJ). Critically, these repair mechanisms do not operate in isolation and evidence for interplay between pathways and repair associated with replication is discussed. Importantly, characterising non-canonical functions of key proteins and understanding the bespoke pathways used to tolerate, repair or bypass DNA damage will be fundamental in fully understanding the causes of mitochondrial genome mutations and mitochondrial dysfunction.

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CUT Domain Proteins in DNA Repair and Cancer

Cancers ◽

10.3390/cancers13122953 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2953

Author(s):

Zubaidah M. Ramdzan ◽

Elise Vickridge ◽

Camila C. F. Faraco ◽

Alain Nepveu

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Oxidative Dna Damage ◽

Excision Repair ◽

Ras Pathway ◽

Synthetic Lethal ◽

Activating Mutations ◽

Elevated Expression ◽

Base Excision

Recent studies revealed that CUT domains function as accessory factors that accelerate DNA repair by stimulating the enzymatic activities of the base excision repair enzymes OGG1, APE1, and DNA pol β. Strikingly, the role of CUT domain proteins in DNA repair is exploited by cancer cells to facilitate their survival. Cancer cells in which the RAS pathway is activated produce an excess of reactive oxygen species (ROS) which, if not counterbalanced by increased production of antioxidants, causes sustained oxidative DNA damage and, ultimately, cell senescence. These cancer cells can adapt by increasing their capacity to repair oxidative DNA damage in part through elevated expression of CUT domain proteins such as CUX1, CUX2, or SATB1. In particular, CUX1 overexpression was shown to cooperate with RAS in the formation of mammary and lung tumors in mice. Conversely, knockdown of CUX1, CUX2, or SATB1 was found to be synthetic lethal in cancer cells exhibiting high ROS levels as a consequence of activating mutations in KRAS, HRAS, BRAF, or EGFR. Importantly, as a byproduct of their adaptation, cancer cells that overexpress CUT domain proteins exhibit increased resistance to genotoxic treatments such as ionizing radiation, temozolomide, and cisplatin.

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