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International Review of Cell and... 2020There is much interest in targeting DNA repair pathways for use in cancer therapy, as the effectiveness of many therapeutic agents relies on their ability to cause... (Review)
Review
There is much interest in targeting DNA repair pathways for use in cancer therapy, as the effectiveness of many therapeutic agents relies on their ability to cause damage to DNA, and deficiencies in DSB repair pathways can make cells more sensitive to specific cancer therapies. For example, defects in the double-strand break (DSB) pathways, non-homologous end joining (NHEJ) and homology-directed repair (HDR), induce sensitivity to radiation therapy and poly(ADP)-ribose polymerase (PARP) inhibitors, respectively. However, traditional approaches to inhibit DNA repair through small molecule inhibitors have often been limited by toxicity and poor bioavailability. This review identifies several pharmacologic manipulations that modulate DSB repair by reducing expression of DNA repair factors. A number of pathways have been identified that modulate activity of NHEJ and HDR through this mechanism, including growth and hormonal receptor signaling pathways as well as epigenetic modifiers. We also discuss the effects of anti-angiogenic therapy on DSB repair. Preclinically, these pharmacological manipulations of DNA repair factor expression have been shown to increase sensitivity to specific cancer therapies, including ionizing radiation and PARP inhibitors. When applicable, relevant clinical trials are discussed and areas for future study are identified.
Topics: Angiogenesis Inhibitors; Animals; DNA Breaks, Double-Stranded; DNA Repair; Histone Deacetylase Inhibitors; Humans; Phosphoinositide-3 Kinase Inhibitors; Transcriptional Activation
PubMed: 32475473
DOI: 10.1016/bs.ircmb.2019.11.003 -
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 -
Annual Review of Medicine 2015Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of... (Review)
Review
Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of molecular pathways governing DNA damage signaling and DNA repair in response to different types of DNA lesions allows for a better understanding of the effects of radiation and chemotherapy on normal and tumor cells. Although dysregulation of the DNA damage response (DDR) is associated with predisposition to cancer development, it can also result in hypersensitivity or resistance of tumors to therapy and can be exploited for improvement of cancer treatment. We highlight the DDR pathways that are activated after treatment with radiation and different classes of chemotherapeutic drugs and describe mechanisms determining tumor sensitivity and resistance to these agents. Further, we discuss approaches to enhance tumor sensitivity to radiation and chemotherapy by modulating the DDR with a goal of enhancing the effectiveness of cancer therapies.
Topics: Antineoplastic Agents; DNA Damage; DNA Methylation; DNA Repair; Humans; Neoplasms; Radiotherapy
PubMed: 25423595
DOI: 10.1146/annurev-med-081313-121208 -
Current Opinion in Genetics &... Jun 1993The sequence and functional homology of certain genes between mammalian and non-mammalian eukaryotes has facilitated significant advances in our understanding of... (Review)
Review
The sequence and functional homology of certain genes between mammalian and non-mammalian eukaryotes has facilitated significant advances in our understanding of mammalian DNA repair. Several novel DNA damage and repair genes have been identified by using a variety of approaches. Study of these genes will lead to an increased understanding of the biological consequences of aberrant DNA maintenance in humans and other species.
Topics: Animals; DNA Repair; Humans; Mammals
PubMed: 8353423
DOI: 10.1016/0959-437x(93)90122-6 -
British Journal of Cancer Mar 2020Effective DNA repair is essential for cell survival: a failure to correctly repair damage leads to the accumulation of mutations and is the driving force for... (Review)
Review
Effective DNA repair is essential for cell survival: a failure to correctly repair damage leads to the accumulation of mutations and is the driving force for carcinogenesis. Multiple pathways have evolved to protect against both intrinsic and extrinsic genotoxic events, and recent developments have highlighted an unforeseen critical role for RNA in ensuring genome stability. It is currently unclear exactly how RNA molecules participate in the repair pathways, although many models have been proposed and it is possible that RNA acts in diverse ways to facilitate DNA repair. A number of well-documented DNA repair factors have been described to have RNA-binding capacities and, moreover, screens investigating DNA-damage repair mechanisms have identified RNA-binding proteins as a major group of novel factors involved in DNA repair. In this review, we integrate some of these datasets to identify commonalities that might highlight novel and interesting factors for future investigations. This emerging role for RNA opens up a new dimension in the field of DNA repair; we discuss its impact on our current understanding of DNA repair processes and consider how it might influence cancer progression.
Topics: Animals; DNA; DNA Breaks, Double-Stranded; DNA Repair; Humans; RNA
PubMed: 31894141
DOI: 10.1038/s41416-019-0624-1 -
Seminars in Cancer Biology Nov 2021Arsenic is widely present in the environment and is associated with various population health risks including cancers. Arsenic exposure at environmentally relevant... (Review)
Review
Arsenic is widely present in the environment and is associated with various population health risks including cancers. Arsenic exposure at environmentally relevant levels enhances the mutagenic effect of other carcinogens such as ultraviolet radiation. Investigation on the molecular mechanisms could inform the prevention and intervention strategies of arsenic carcinogenesis and co-carcinogenesis. Arsenic inhibition of DNA repair has been demonstrated to be an important mechanism, and certain DNA repair proteins have been identified to be extremely sensitive to arsenic exposure. This review will summarize the recent advances in understanding the mechanisms of arsenic carcinogenesis and co-carcinogenesis, including DNA damage induction and ROS generation, particularly how arsenic inhibits DNA repair through an integrated molecular mechanism which includes its interactions with sensitive zinc finger DNA repair proteins.
Topics: Animals; Arsenic; Cocarcinogenesis; DNA Repair; Humans; Zinc Fingers
PubMed: 33984503
DOI: 10.1016/j.semcancer.2021.05.009 -
Journal of the National Cancer Institute Nov 2017Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations... (Review)
Review
Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.
Topics: Antineoplastic Agents; DNA End-Joining Repair; DNA Mismatch Repair; DNA Repair; Genes, BRCA1; Genes, BRCA2; Homologous Recombination; Humans; Molecular Targeted Therapy; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Synthetic Lethal Mutations
PubMed: 28521333
DOI: 10.1093/jnci/djx059 -
Asian Journal of Andrology 2021Programmed DNA double-strand breaks (DSBs) are necessary for meiosis in mammals. A sufficient number of DSBs ensure the normal pairing/synapsis of homologous... (Review)
Review
Programmed DNA double-strand breaks (DSBs) are necessary for meiosis in mammals. A sufficient number of DSBs ensure the normal pairing/synapsis of homologous chromosomes. Abnormal DSB repair undermines meiosis, leading to sterility in mammals. The DSBs that initiate recombination are repaired as crossovers and noncrossovers, and crossovers are required for correct chromosome separation. Thus, the placement, timing, and frequency of crossover formation must be tightly controlled. Importantly, mutations in many genes related to the formation and repair of DSB result in infertility in humans. These mutations cause nonobstructive azoospermia in men, premature ovarian insufficiency and ovarian dysgenesis in women. Here, we have illustrated the formation and repair of DSB in mammals, summarized major factors influencing the formation of DSB and the theories of crossover regulation.
Topics: Animals; Chromosome Segregation; DNA Breaks, Double-Stranded; DNA Repair; Humans; Mammals
PubMed: 34708719
DOI: 10.4103/aja202191 -
Cancer Metastasis Reviews Dec 2010Many cytotoxic agents used in cancer treatment exert their effects through their ability to directly or indirectly damage DNA and thus resulting in cell death. Major... (Review)
Review
Many cytotoxic agents used in cancer treatment exert their effects through their ability to directly or indirectly damage DNA and thus resulting in cell death. Major types of DNA damage induced by anticancer treatment include strand breaks (double or single strand), crosslinks (inter-strand, intra-strand, DNA-protein crosslinks), and interference with nucleotide metabolism and DNA synthesis. On the other hand, cancer cells activate various DNA repair pathways and repair DNA damages induced by cytotoxic drugs. The purpose of the current review is to present the major types of DNA damage induced by cytotoxic agents, DNA repair pathways, and their role as predictive agents, as well as evaluate the future perspectives of the novel DNA repair pathways inhibitors in cancer therapeutics.
Topics: Antineoplastic Agents; DNA Damage; DNA Repair; Humans; Neoplasms
PubMed: 20821251
DOI: 10.1007/s10555-010-9258-8 -
European Journal of Cancer (Oxford,... Sep 2011
Review
Topics: Antineoplastic Agents; DNA Repair; Genomic Instability; Humans; Molecular Targeted Therapy; Neoplasms; Signal Transduction
PubMed: 21944004
DOI: 10.1016/S0959-8049(11)70192-7