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International Journal of Molecular... Mar 2022The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different... (Review)
Review
The repair of DNA damage is a crucial process for the correct maintenance of genetic information, thus, allowing the proper functioning of cells. Among the different types of lesions occurring in DNA, double-strand breaks (DSBs) are considered the most harmful type of lesion, which can result in significant loss of genetic information, leading to diseases, such as cancer. DSB repair occurs through two main mechanisms, called non-homologous end joining (NHEJ) and homologous recombination repair (HRR). There is evidence showing that miRNAs play an important role in the regulation of genes acting in NHEJ and HRR mechanisms, either through direct complementary binding to mRNA targets, thus, repressing translation, or by targeting other genes involved in the transcription and activity of DSB repair genes. Therefore, alteration of miRNA expression has an impact on the ability of cells to repair DSBs, which, in turn, affects cancer therapy sensitivity. This latter gives account of the importance of miRNAs as regulators of NHEJ and HRR and places them as a promising target to improve cancer therapy. Here, we review recent reports demonstrating an association between miRNAs and genes involved in NHEJ and HRR. We employed the Web of Science search query TS ("gene official symbol/gene aliases*" AND "miRNA/microRNA/miR-") and focused on articles published in the last decade, between 2010 and 2021. We also performed a data analysis to represent miRNA-mRNA validated interactions from TarBase v.8, in order to offer an updated overview about the role of miRNAs as regulators of DSB repair.
Topics: DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; MicroRNAs; RNA, Messenger; Recombinational DNA Repair
PubMed: 35328651
DOI: 10.3390/ijms23063231 -
DNA Repair Jul 2024Multiple separate repair mechanisms safeguard the genome against various types of DNA damage, and their failure can increase the rate of spontaneous mutagenesis. The... (Review)
Review
Multiple separate repair mechanisms safeguard the genome against various types of DNA damage, and their failure can increase the rate of spontaneous mutagenesis. The malfunction of distinct repair mechanisms leads to genomic instability through different mutagenic processes. For example, defective mismatch repair causes high base substitution rates and microsatellite instability, whereas homologous recombination deficiency is characteristically associated with deletions and chromosome instability. This review presents a comprehensive collection of all mutagenic phenotypes associated with the loss of each DNA repair mechanism, drawing on data from a variety of model organisms and mutagenesis assays, and placing greatest emphasis on systematic analyses of human cancer datasets. We describe the latest theories on the mechanism of each mutagenic process, often explained by reliance on an alternative repair pathway or the error-prone replication of unrepaired, damaged DNA. Aided by the concept of mutational signatures, the genomic phenotypes can be used in cancer diagnosis to identify defective DNA repair pathways.
Topics: Humans; Mutagenesis; DNA Repair; Animals; Neoplasms; DNA Damage; Genomic Instability; DNA Mismatch Repair
PubMed: 38788323
DOI: 10.1016/j.dnarep.2024.103694 -
Inhibitors of DNA double-strand break repair at the crossroads of cancer therapy and genome editing.Biochemical Pharmacology Dec 2020Conventional cancer treatment modalities such as radiation and chemotherapy, cause cancer cell death by inducing DNA damage, particularly DNA strand breaks. Over the... (Review)
Review
Conventional cancer treatment modalities such as radiation and chemotherapy, cause cancer cell death by inducing DNA damage, particularly DNA strand breaks. Over the years, newer avenues have emerged for overcoming radio/chemoresistance by harnessing repair proteins as targets for small molecule inhibitors. Analysis of genome-wide expression data in cancer subtypes and understanding synthetic lethal interactions among repair pathways are important stepping-stones. Several inhibitors targeting DNA strand break repair proteins have yielded good effects in preclinical studies, and have the potential to be developed as therapeutics in cancer as monotherapy or in combination with radiation and chemotherapy. Furthermore, these small molecule inhibitors can aid in precise genome editing (using CRISPR) by harnessing the differential levels of repair inside cells. Shifting the repair balance towards homology-directed repair using inhibitors of NHEJ or stimulators of HR has yielded promising effects alongside CRISPR in cells and several disease models. In short, DNA strand break repair inhibitors are the forerunners in cancer therapy and genome editing, working in concert with the established artillery in the field.
Topics: Animals; Antineoplastic Agents; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Gene Editing; Humans; Neoplasms
PubMed: 32798465
DOI: 10.1016/j.bcp.2020.114195 -
The CRISPR Journal Dec 2021
Topics: CRISPR-Cas Systems; DNA Damage; DNA Repair; Gene Editing
PubMed: 34935489
DOI: 10.1089/crispr.2021.29140.dme -
Journal of Dermatological Science Jun 2008The incidence of sunlight-induced skin changes (photoaged skin, skin carcinogenesis) increases with increasing age and it is thought to be associated with an... (Review)
Review
The incidence of sunlight-induced skin changes (photoaged skin, skin carcinogenesis) increases with increasing age and it is thought to be associated with an accumulation of mutations in skin cells. These mutations are mainly caused by UV exposure. The reactive oxygen species produced in UV-exposed skin can cause various kinds of DNA damages e.g., 8-oxoguanine, which are primarily repaired by the base excision repair (BER) system. In addition, UV can directly cause DNA damages; cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts (6-4PP), both of which can be repaired by the nucleotide excision repair (NER) system. There have been several reports showing an age-related reduction in the DNA repair capacity in the NER, BER, and other repair systems, which contributes to the phenotypes of aging. To clarify the mechanism of skin aging, we examined the NER of skin fibroblasts from healthy donors of different ages. In a host cell reactivation assay, the cells from elderly donors exhibited a significant decline in the ability to restore transfected reporter DNA damaged by UV. In contrast, the ability to remove CPD and 6-4PP declined little with age, as assessed by an enzyme-linked immunosorbent assay. The mRNA expression of DNA repair synthesis-related genes was markedly decreased in the cells from elderly subjects as compared with those from young subjects. These results imply that the age-sensitive step took place after the damage excision in the NER, and that there is an impairment of the latter step of the NER in aging. Based on our data, as well as other reports, the reduced post-UV DNA repair capacity in aging resulting in an accumulation of UV-induced DNA damage is thus considered to be associated with the phenotypes of photoaged skin.
Topics: DNA Repair; Humans; Skin Aging
PubMed: 17920816
DOI: 10.1016/j.jdermsci.2007.08.011 -
International Journal of Molecular... Nov 2017Autophagy and DNA repair are biological processes vital for cellular homeostasis maintenance and when dysfunctional, they lead to several human disorders including... (Review)
Review
Autophagy and DNA repair are biological processes vital for cellular homeostasis maintenance and when dysfunctional, they lead to several human disorders including premature aging, neurodegenerative diseases, and cancer. The interchange between these pathways is complex and it may occur in both directions. Autophagy is activated in response to several DNA lesions types and it can regulate different mechanisms and molecules involved in DNA damage response (DDR), such as cell cycle checkpoints, cell death, and DNA repair. Thus, autophagy may modulate DNA repair pathways, the main focus of this review. In addition to the already well-documented autophagy positive effects on homologous recombination (HR), autophagy has also been implicated with other DNA repair mechanisms, such as base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Given the relevance of these cellular processes, the clinical applications of drugs targeting this autophagy-DNA repair interface emerge as potential therapeutic strategies for many diseases, especially cancer.
Topics: Animals; Autophagy; DNA End-Joining Repair; DNA Repair; Homologous Recombination; Humans
PubMed: 29112132
DOI: 10.3390/ijms18112351 -
Diversity upon diversity: linking DNA double-strand break repair to blood cancer health disparities.Trends in Cancer Apr 2022Chromosomal translocations arising from aberrant repair of multiple DNA double-strand breaks (DSBs) are a defining characteristic of many cancers. DSBs are an essential... (Review)
Review
Chromosomal translocations arising from aberrant repair of multiple DNA double-strand breaks (DSBs) are a defining characteristic of many cancers. DSBs are an essential part of physiological processes in antibody-producing B cells. The B cell environment is poised to generate genome instability leading to translocations relevant to the pathology of blood cancers. These are a diverse set of cancers, but limited data from under-represented groups have pointed to health disparities associated with each. We focus on the DSBs that occur in developing B cells and propose the most likely mechanism behind the formation of translocations. We also highlight specific cancers in which these rearrangements occur and address the growing concern of health disparities associated with them.
Topics: DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Humans; Neoplasms
PubMed: 35094960
DOI: 10.1016/j.trecan.2022.01.003 -
Acta Biochimica Et Biophysica Sinica Dec 2023DNA double-strand break (DSB) repair by homologous recombination (HR) is crucial for the maintenance of genome stability and integrity. In this study, we aim to identify...
DNA double-strand break (DSB) repair by homologous recombination (HR) is crucial for the maintenance of genome stability and integrity. In this study, we aim to identify novel RNA binding proteins (RBPs) involved in HR repair because little is known about RBP function in HR. For this purpose, we carry out pulldown assays using a synthetic ssDNA/dsDNA structure coated with replication protein A (RPA) to mimic resected DNA, a crucial intermediate in HR-mediated DSB repair. Using this approach, we identify RNA-binding motif protein 14 (RBM14) as a potential binding partner. We further show that RBM14 interacts with an essential HR repair factor, CtIP. RBM14 is crucial for CtIP recruitment to DSB sites and for subsequent RPA coating and RAD51 replacement, facilitating efficient HR repair. Moreover, inhibition of RBM14 expression sensitizes cancer cells to X-ray irradiation. Together, our results demonstrate that RBM14 promotes DNA end resection to ensure HR repair and may serve as a potential target for cancer therapy.
Topics: Recombinational DNA Repair; DNA Breaks, Double-Stranded; DNA Repair; Homologous Recombination; Replication Protein A; DNA; DNA End-Joining Repair
PubMed: 37559455
DOI: 10.3724/abbs.2023104 -
Cells Apr 2021bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or... (Review)
Review
bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in . Among various species, has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in .
Topics: DNA Repair; Deinococcus; Gene Expression Regulation, Bacterial; Mutagenesis; Radiation Tolerance; SOS Response, Genetics
PubMed: 33923690
DOI: 10.3390/cells10040924 -
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