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Genes & Development Mar 2022DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to... (Review)
Review
DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repair and signaling activities. Here, we review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. Furthermore, we discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.
Topics: DNA Damage; DNA Repair; Genomic Instability; Humans; Immunotherapy; Neoplasms
PubMed: 35318271
DOI: 10.1101/gad.349431.122 -
Cells Jul 2020DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of... (Review)
Review
DNA is the source of genetic information, and preserving its integrity is essential in order to sustain life. The genome is continuously threatened by different types of DNA lesions, such as abasic sites, mismatches, interstrand crosslinks, or single-stranded and double-stranded breaks. As a consequence, cells have evolved specialized DNA damage response (DDR) mechanisms to sustain genome integrity. By orchestrating multilayer signaling cascades specific for the type of lesion that occurred, the DDR ensures that genetic information is preserved overtime. In the last decades, DNA repair mechanisms have been thoroughly investigated to untangle these complex networks of pathways and processes. As a result, key factors have been identified that control and coordinate DDR circuits in time and space. In the first part of this review, we describe the critical processes encompassing DNA damage sensing and resolution. In the second part, we illustrate the consequences of partial or complete failure of the DNA repair machinery. Lastly, we will report examples in which this knowledge has been instrumental to develop novel therapies based on genome editing technologies, such as CRISPR-Cas.
Topics: Animals; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Damage; DNA Repair; Gene Editing; Humans
PubMed: 32664329
DOI: 10.3390/cells9071665 -
Annual Review of Genetics Nov 2021DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genome integrity and cell viability. Typically, cells repair DSBs by either nonhomologous end joining... (Review)
Review
DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genome integrity and cell viability. Typically, cells repair DSBs by either nonhomologous end joining (NHEJ) or homologous recombination (HR). The relative use of these two pathways depends on many factors, including cell cycle stage and the nature of the DNA ends. A critical determinant of repair pathway selection is the initiation of 5'→3' nucleolytic degradation of DNA ends, a process referred to as DNA end resection. End resection is essential to create single-stranded DNA overhangs, which serve as the substrate for the Rad51 recombinase to initiate HR and are refractory to NHEJ repair. Here, we review recent insights into the mechanisms of end resection, how it is regulated, and the pathological consequences of its dysregulation.
Topics: DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; DNA-Binding Proteins; Exodeoxyribonucleases; Homologous Recombination
PubMed: 34813349
DOI: 10.1146/annurev-genet-071719-020312 -
Critical Reviews in Food Science and... 2020Due to change in lifestyle and food habits, people are more at risk of diet-related diseases and cancers. It is also established that dietary modifications significantly... (Review)
Review
Due to change in lifestyle and food habits, people are more at risk of diet-related diseases and cancers. It is also established that dietary modifications significantly reduce the risk of diseases. Nutrigenomics is relatively fresh discipline, but possess an enormous potential that can apply for prevention and management of certain carcinomas and diseases. This review enables us to generate useful information for scientists and health professionals regarding the role of Nutrigenomics in the prevention of diet and lifestyle-related diseases like cancer. It influences health conditions of individuals and susceptibility of disease by defining the metabolic response and gene expression. Epigenetic modifications can perform a significant role in disease occurrence and pathogenesis. DNA methylation and chromatin remodeling are the most common epigenetic mechanisms. Omega 3 fatty acids are the best example of nutrients and gene interaction not involving DNA methylation while certain bioactive food compounds have a proven role in cancer prevention through an epigenetic mechanism. Dietary polyphenols substantially take part in prevention of oral, breast, skin, esophageal, colorectal, prostate, pancreatic and lung cancers. Moreover, minerals and vitamins involve regulatory processes. Zinc, Selenium and folate involve in DNA repairing process have anticancer properties. Consumption of multivitamins prevents methylation of cancer cells.
Topics: DNA Methylation; DNA Repair; Diet; Epigenesis, Genetic; Humans; Neoplasms; Nutrigenomics
PubMed: 30729798
DOI: 10.1080/10408398.2019.1571480 -
Nature Reviews. Molecular Cell Biology Jul 2023All organisms possess molecular mechanisms that govern DNA repair and associated DNA damage response (DDR) processes. Owing to their relevance to human disease, most... (Review)
Review
All organisms possess molecular mechanisms that govern DNA repair and associated DNA damage response (DDR) processes. Owing to their relevance to human disease, most notably cancer, these mechanisms have been studied extensively, yet new DNA repair and/or DDR factors and functional interactions between them are still being uncovered. The emergence of CRISPR technologies and CRISPR-based genetic screens has enabled genome-scale analyses of gene-gene and gene-drug interactions, thereby providing new insights into cellular processes in distinct DDR-deficiency genetic backgrounds and conditions. In this Review, we discuss the mechanistic basis of CRISPR-Cas genetic screening approaches and describe how they have contributed to our understanding of DNA repair and DDR pathways. We discuss how DNA repair pathways are regulated, and identify and characterize crosstalk between them. We also highlight the impacts of CRISPR-based studies in identifying novel strategies for cancer therapy, and in understanding, overcoming and even exploiting cancer-drug resistance, for example in the contexts of PARP inhibition, homologous recombination deficiencies and/or replication stress. Lastly, we present the DDR CRISPR screen (DDRcs) portal , in which we have collected and reanalysed data from CRISPR screen studies and provide a tool for systematically exploring them.
Topics: Humans; CRISPR-Cas Systems; DNA Repair; Neoplasms; Genome; DNA Damage
PubMed: 36781955
DOI: 10.1038/s41580-022-00571-x -
Molecular Cell Jun 2020Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects... (Review)
Review
Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies.
Topics: Animals; Antineoplastic Agents; Biomarkers, Pharmacological; DNA Damage; DNA End-Joining Repair; DNA Repair; Genes, BRCA1; Homologous Recombination; Humans; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 32459988
DOI: 10.1016/j.molcel.2020.04.035 -
Modern Pathology : An Official Journal... Mar 2023The repair of DNA double-stranded breaks relies on the homologous recombination repair pathway and is critical to cell function. However, this pathway can be lost in... (Review)
Review
The repair of DNA double-stranded breaks relies on the homologous recombination repair pathway and is critical to cell function. However, this pathway can be lost in some cancers such as breast, ovarian, endometrial, pancreatic, and prostate cancers. Cancer cells with homologous recombination deficiency (HRD) are sensitive to targeted inhibition of poly-ADP ribose polymerase (PARP), a key component of alternative backup DNA repair pathways. Identifying patients with cancer with HRD biomarkers allows the identification of patients likely to benefit from PARP inhibitor therapies. In this study, we describe the causes of HRD, the underlying molecular changes resulting from HRD that form the basis of different molecular HRD assays, and discuss the issues around their clinical use. This overview is directed toward practicing pathologists wishing to be informed of this new predictive biomarker, as PARP inhibitors are increasingly used in standard care settings.
Topics: Female; Humans; Recombinational DNA Repair; Ovarian Neoplasms; Homologous Recombination; Pathologists; DNA Repair
PubMed: 36788098
DOI: 10.1016/j.modpat.2022.100049 -
Nature Reviews. Molecular Cell Biology Dec 2020Non-homologous DNA end joining (NHEJ) is the predominant repair mechanism of any type of DNA double-strand break (DSB) during most of the cell cycle and is essential for... (Review)
Review
Non-homologous DNA end joining (NHEJ) is the predominant repair mechanism of any type of DNA double-strand break (DSB) during most of the cell cycle and is essential for the development of antigen receptors. Defects in NHEJ result in sensitivity to ionizing radiation and loss of lymphocytes. The most critical step of NHEJ is synapsis, or the juxtaposition of the two DNA ends of a DSB, because all subsequent steps rely on it. Recent findings show that, like the end processing step, synapsis can be achieved through several mechanisms. In this Review, we first discuss repair pathway choice between NHEJ and other DSB repair pathways. We then integrate recent insights into the mechanisms of NHEJ synapsis with updates on other steps of NHEJ, such as DNA end processing and ligation. Finally, we discuss NHEJ-related human diseases, including inherited disorders and neoplasia, which arise from rare failures at different NHEJ steps.
Topics: Animals; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Disease; Genetic Diseases, Inborn; Humans; Neoplasms; Signal Transduction
PubMed: 33077885
DOI: 10.1038/s41580-020-00297-8 -
Frontiers in Immunology 2022
Topics: DNA Damage; DNA Repair; Immunity
PubMed: 36254318
DOI: 10.3389/fimmu.2022.1034689 -
Biomolecules Dec 2022Developing B and T lymphocytes requires programmed DNA double-strand breaks followed by the activation of the DNA damage response (DDR) pathway and DNA repair [...].
Developing B and T lymphocytes requires programmed DNA double-strand breaks followed by the activation of the DNA damage response (DDR) pathway and DNA repair [...].
Topics: DNA Damage; DNA Repair; DNA Breaks, Double-Stranded; T-Lymphocytes
PubMed: 36671469
DOI: 10.3390/biom13010084