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International Journal of Molecular... Jul 2017Genomic DNA is compacted into chromatin through packaging with histone and non-histone proteins. Importantly, DNA accessibility is dynamically regulated to ensure genome... (Review)
Review
Genomic DNA is compacted into chromatin through packaging with histone and non-histone proteins. Importantly, DNA accessibility is dynamically regulated to ensure genome stability. This is exemplified in the response to DNA damage where chromatin relaxation near genomic lesions serves to promote access of relevant enzymes to specific DNA regions for signaling and repair. Furthermore, recent data highlight genome maintenance roles of chromatin through the regulation of endogenous DNA-templated processes including transcription and replication. Here, we review research that shows the importance of chromatin structure regulation in maintaining genome integrity by multiple mechanisms including facilitating DNA repair and directly suppressing endogenous DNA damage.
Topics: Animals; Chromatin Assembly and Disassembly; DNA Damage; DNA Repair; DNA Replication; Genomic Instability; Humans
PubMed: 28698521
DOI: 10.3390/ijms18071486 -
DNA Repair Sep 2020Trinucleotide repeat (TNR) instability is the cause of over 40 human neurodegenerative diseases and certain types of cancer. TNR instability can result from DNA... (Review)
Review
Trinucleotide repeat (TNR) instability is the cause of over 40 human neurodegenerative diseases and certain types of cancer. TNR instability can result from DNA replication, repair, recombination, and gene transcription. Emerging evidence indicates that DNA base damage and base excision repair (BER) play an active role in regulating somatic TNR instability. These processes may potentially modulate the onset and progression of TNR-related diseases, given that TNRs are hotspots of DNA base damage that are present in mammalian cells with a high frequency. In this review, we discuss the recent advances in our understanding of the molecular mechanisms underlying BER-mediated TNR instability. We initially discuss the roles of the BER pathway and locations of DNA base lesions in TNRs and their interplay with non-B form DNA structures in governing repeat instability. We then discuss how the coordinated activities of BER enzymes can modulate a balance between the removal and addition of TNRs to regulate somatic TNR instability. We further discuss how this balance can be disrupted by the crosstalk between BER and DNA mismatch repair (MMR) machinery resulting in TNR expansion. Finally, we suggest future directions regarding BER-mediated somatic TNR instability and its association with TNR disease prevention and treatment.
Topics: Animals; DNA; DNA Damage; DNA Mismatch Repair; DNA Repair; Humans; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 33087278
DOI: 10.1016/j.dnarep.2020.102912 -
Pharmacology & Therapeutics Aug 2018DNA repair pathways are evolutionarily conserved molecular mechanisms that maintain the integrity of genomic DNA. In cancer therapies, the integrity and activity of DNA... (Review)
Review
DNA repair pathways are evolutionarily conserved molecular mechanisms that maintain the integrity of genomic DNA. In cancer therapies, the integrity and activity of DNA repair pathways predict therapy resistance and disease outcome. Members of the poly (ADP-ribose) polymerase (PARP) family initiate and organize the biologic process of DNA repair, which counteracts many types of chemotherapies. Since the first development in approximately 3 decades ago, PARP inhibitors have greatly changed the concept of cancer therapy, leading to encouraging improvements in tumor suppression and disease outcomes. Here we summaries both pre-clinical and clinical findings of PARP inhibitors applications, particularly for combination therapies.
Topics: Animals; Combined Modality Therapy; DNA Repair; Drug Resistance, Neoplasm; Humans; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Temozolomide
PubMed: 29621593
DOI: 10.1016/j.pharmthera.2018.03.006 -
International Journal of Molecular... Aug 2023The critical role of the DNA repair system in preserving the health and survival of living organisms is widely recognized as dysfunction within this system can result in... (Review)
Review
The critical role of the DNA repair system in preserving the health and survival of living organisms is widely recognized as dysfunction within this system can result in a broad range of severe conditions, including neurodegenerative diseases, blood disorders, infertility, and cancer. Despite comprehensive research on the molecular and cellular mechanisms of DNA repair pathways, there remains a significant knowledge gap concerning these processes at an organismal level. The teleost zebrafish has emerged as a powerful model organism for investigating these intricate DNA repair mechanisms. Their utility arises from a combination of their well-characterized genomic information, the ability to visualize specific phenotype outcomes in distinct cells and tissues, and the availability of diverse genetic experimental approaches. In this review, we provide an in-depth overview of recent advancements in our understanding of the in vivo roles of DNA repair pathways. We cover a variety of critical biological processes including neurogenesis, hematopoiesis, germ cell development, tumorigenesis, and aging, with a specific emphasis on findings obtained from the use of zebrafish as a model system. Our comprehensive review highlights the importance of zebrafish in enhancing our understanding of the functions of DNA repair systems at the organismal level and paves the way for future investigations in this field.
Topics: Animals; Zebrafish; Aging; Carcinogenesis; Cell Differentiation; DNA Repair
PubMed: 37685935
DOI: 10.3390/ijms241713120 -
Biomolecules Oct 2015Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery,... (Review)
Review
Heat shock protein 90 (Hsp90) is an evolutionary conserved molecular chaperone that, together with Hsp70 and co-chaperones makes up the Hsp90 chaperone machinery, stabilizing and activating more than 200 proteins, involved in protein homeostasis (i.e., proteostasis), transcriptional regulation, chromatin remodeling, and DNA repair. Cells respond to DNA damage by activating complex DNA damage response (DDR) pathways that include: (i) cell cycle arrest; (ii) transcriptional and post-translational activation of a subset of genes, including those associated with DNA repair; and (iii) triggering of programmed cell death. The efficacy of the DDR pathways is influenced by the nuclear levels of DNA repair proteins, which are regulated by balancing between protein synthesis and degradation as well as by nuclear import and export. The inability to respond properly to either DNA damage or to DNA repair leads to genetic instability, which in turn may enhance the rate of cancer development. Multiple components of the DNA double strand breaks repair machinery, including BRCA1, BRCA2, CHK1, DNA-PKcs, FANCA, and the MRE11/RAD50/NBN complex, have been described to be client proteins of Hsp90, which acts as a regulator of the diverse DDR pathways. Inhibition of Hsp90 actions leads to the altered localization and stabilization of DDR proteins after DNA damage and may represent a cell-specific and tumor-selective radiosensibilizer. Here, the role of Hsp90-dependent molecular mechanisms involved in cancer onset and in the maintenance of the genome integrity is discussed and highlighted.
Topics: DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; HSP90 Heat-Shock Proteins; Humans
PubMed: 26501335
DOI: 10.3390/biom5042589 -
Trends in Cancer Nov 2016Maintenance of genomic integrity is critical for adaptive survival in the face of endogenous and exogenous environmental stress. The loss of stability and fidelity in... (Review)
Review
Maintenance of genomic integrity is critical for adaptive survival in the face of endogenous and exogenous environmental stress. The loss of stability and fidelity in the genome caused by cancer and cancer treatment provides therapeutic opportunities to leverage the critical balance between DNA injury and repair. Blocking repair and pushing damaged DNA through the cell cycle using therapeutic inhibitors exemplify the 'pushmi-pullyu' effect of disrupted DNA repair. DNA repair inhibitors (DNARi) can be separated into five biofunctional categories: sensors, mediators, transducers, effectors, and collaborators that recognize DNA damage, propagate injury DNA messages, regulate cell cycle checkpoints, and alter the microenvironment. The result is cancer therapeutics that takes advantage of clinical synthetic lethality, resulting in selective tumor cell kill. Here, we review recent considerations related to DNA repair and new DNARi agents and organize those findings to address future directions and clinical opportunities.
Topics: Animals; Antineoplastic Agents; DNA Damage; DNA Repair; Humans; Synthetic Lethal Mutations
PubMed: 28741503
DOI: 10.1016/j.trecan.2016.10.014 -
Proceedings of the National Academy of... Oct 2016Cisplatin is a major anticancer drug that kills cancer cells by damaging their DNA. Cancer cells cope with the drug by removal of the damages with nucleotide excision...
Cisplatin is a major anticancer drug that kills cancer cells by damaging their DNA. Cancer cells cope with the drug by removal of the damages with nucleotide excision repair. We have developed methods to measure cisplatin adduct formation and its repair at single-nucleotide resolution. "Damage-seq" relies on the replication-blocking properties of the bulky base lesions to precisely map their location. "XR-seq" independently maps the removal of these damages by capturing and sequencing the excised oligomer released during repair. The damage and repair maps we generated reveal that damage distribution is essentially uniform and is dictated mostly by the underlying sequence. In contrast, cisplatin repair is heterogeneous in the genome and is affected by multiple factors including transcription and chromatin states. Thus, the overall effect of damages in the genome is primarily driven not by damage formation but by the repair efficiency. The combination of the Damage-seq and XR-seq methods has the potential for developing novel cancer therapeutic strategies.
Topics: Base Sequence; Cell Line; Cisplatin; DNA Damage; DNA Repair; Genome, Human; Humans; Nucleosomes; Nucleotides
PubMed: 27688757
DOI: 10.1073/pnas.1614430113 -
DNA Repair Oct 2023DNA double-stranded breaks (DSBs) are a particularly challenging form of DNA damage to repair because the damaged DNA must not only undergo the chemical reactions...
DNA double-stranded breaks (DSBs) are a particularly challenging form of DNA damage to repair because the damaged DNA must not only undergo the chemical reactions responsible for returning it to its original state, but, additionally, the two free ends can become physically separated in the nucleus and must be bridged prior to repair. In nonhomologous end joining (NHEJ), one of the major pathways of DSB repair, repair is carried out by a number of repair factors capable of binding to and directly joining DNA ends. It has been unclear how these processes are carried out at a molecular level, owing in part to the lack of structural evidence describing the coordination of the NHEJ factors with each other and a DNA substrate. Advances in cryo-Electron Microscopy (cryo-EM), allowing for the structural characterization of large protein complexes that would be intractable using other techniques, have led to the visualization several key steps of the NHEJ process, which support a model of sequential assembly of repair factors at the DSB, followed by end-bridging mediated by protein-protein complexes and transition to full synapsis. Here we examine the structural evidence for these models, devoting particular attention to recent work identifying a new NHEJ intermediate state and incorporating new NHEJ factors into the general mechanism. We also discuss the evolving understanding of end-bridging mechanisms in NHEJ and DNA-PKcs's role in mediating DSB repair.
Topics: Cryoelectron Microscopy; DNA End-Joining Repair; DNA Repair; DNA Breaks, Double-Stranded; DNA
PubMed: 37556875
DOI: 10.1016/j.dnarep.2023.103547 -
BioMed Research International 2020Ionising radiation- (IR-) induced DNA double-strand breaks (DSBs) are considered to be the deleterious DNA lesions that pose a serious threat to genomic stability. The... (Review)
Review
Ionising radiation- (IR-) induced DNA double-strand breaks (DSBs) are considered to be the deleterious DNA lesions that pose a serious threat to genomic stability. The major DNA repair pathways, including classical nonhomologous end joining, homologous recombination, single-strand annealing, and alternative end joining, play critical roles in countering and eliciting IR-induced DSBs to ensure genome integrity. If the IR-induced DNA DSBs are not repaired correctly, the residual or incorrectly repaired DSBs can result in genomic instability that is associated with certain human diseases. Although many efforts have been made in investigating the major mechanisms of IR-induced DNA DSB repair, it is still unclear what determines the choices of IR-induced DNA DSB repair pathways. In this review, we discuss how the mechanisms of IR-induced DSB repair pathway choices can operate in irradiated cells. We first briefly describe the main mechanisms of the major DNA DSB repair pathways and the related key repair proteins. Based on our understanding of the characteristics of IR-induced DNA DSBs and the regulatory mechanisms of DSB repair pathways in irradiated cells and recent advances in this field, We then highlight the main factors and associated challenges to determine the IR-induced DSB repair pathway choices. We conclude that the type and distribution of IR-induced DSBs, chromatin state, DNA-end structure, and DNA-end resection are the main determinants of the choice of the IR-induced DNA DSB repair pathway.
Topics: Animals; Cell Cycle; Chromatin; DNA; DNA Breaks, Double-Stranded; DNA Repair; Genomic Instability; Homologous Recombination; Humans; Radiation, Ionizing
PubMed: 32908893
DOI: 10.1155/2020/4834965 -
DNA Repair Oct 2019DNA double-strand breaks (DSBs) affect chromatin integrity and impact DNA-dependent processes such as transcription. Several studies revealed that the transcription of... (Review)
Review
DNA double-strand breaks (DSBs) affect chromatin integrity and impact DNA-dependent processes such as transcription. Several studies revealed that the transcription of genes located in close proximity to DSBs is transiently repressed. This is achieved through the establishment of either a transient repressive chromatin context or eviction of the RNA polymerase II complex from the damaged chromatin. While these mechanisms of transcription repression have been shown to affect the efficiency and accuracy of DSB repair, it became evident that the transcriptional state of chromatin before DSB formation also influences this process. Moreover, transcription can be initiated from DSB ends, generating long non-coding (lnc)RNAs that will be processed into sequence-specific double-stranded RNAs. These so-called DNA damage-induced (dd)RNAs dictate DSB repair by regulating the accumulation of DNA repair proteins at DSBs. Thus, a complex interplay between mechanisms of transcription activation and repression occurs at DSBs and affects their repair. Here we review our current understanding of the mechanisms that coordinate transcription and DSB repair to prevent genome instability arising from DNA breaks in transcribed regions.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Repair; Humans; Transcription, Genetic
PubMed: 31476573
DOI: 10.1016/j.dnarep.2019.102686