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Cancer Genetics Apr 2021Cancer genome instability arises from diverse defects in DNA-repair machinery, which make cancer cells more susceptible to DNA targeting agents. The interrelation... (Review)
Review
Cancer genome instability arises from diverse defects in DNA-repair machinery, which make cancer cells more susceptible to DNA targeting agents. The interrelation between DNA repair deficiency and the increased effect of DNA targeting agents highlights the double-strand break (DSB) repair, which comprises the homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. The DNA targeting agents are classified into two major groups: non-covalent DNA binding agents and covalent DNA-reactive agents. Although these agents have well-known limitations, such as resistance and secondary carcinogenesis risk, they are extremely important in today's real-life cancer therapy in combination with targeted therapy and immunotherapy. Indeed, DNA targeting drugs are promising therapeutics with a precise application through the background of cancer-specific DNA repair failure. In the current review, the mechanisms of action of diversified DNA-targeting agents, as well as the modulation of DNA repair pathways to increase the DNA-damaging drugs efficacy are presented. Finally, DNA-targeting-based therapies are discussed considering risks, resistance and its uses in the medicine precision era.
Topics: Antineoplastic Agents; Carcinogenesis; DNA Damage; DNA Repair; Humans; Neoplasms; Precision Medicine; Risk Factors
PubMed: 33340831
DOI: 10.1016/j.cancergen.2020.12.002 -
Biomolecules Oct 2022In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased...
In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.
Topics: Humans; Genomic Instability; DNA Repair; DNA End-Joining Repair; Neoplasms; DNA Replication; Chromosome Aberrations
PubMed: 36358918
DOI: 10.3390/biom12111570 -
Environmental and Molecular Mutagenesis Apr 2024Deletions associated with the repair of DNA double-strand breaks is a source of genetic alternation and a recognized source of disease-causing mutagenesis.... (Review)
Review
Deletions associated with the repair of DNA double-strand breaks is a source of genetic alternation and a recognized source of disease-causing mutagenesis. Theta-mediated end joining is a DNA repair mechanism, which guarantees deletions by its employment of microhomology (MH) alignment to facilitate end joining. A lesser-characterized templated insertion ability of this pathway, on the other hand, is associated with both deletion and insertion. This mechanism is characterized by at least one round of polymerase θ-mediated synthesis, which does not result in successful repair, followed by a subsequent round of polymerase engagement and synthesis that does lead to repair. Here we focus on the mechanisms by which polymerase θ introduces these insertions-direct, inverse, and a new class which we have termed strand switching. We observe this new class of templated insertions at multiple loci and across multiple species, often at a comparable frequency to those previously characterized. Templated insertion mutations are often enriched in cancer genomes and repeat expansion disorders. This repair mechanism thus contributes to disease-associated mutagenesis, and may plausibly even promote disease. Characterization of the types of polymerase θ-dependent insertions can provide new insight into these diseases and clinical promise for treatment.
Topics: DNA End-Joining Repair; DNA Repair; DNA Breaks, Double-Stranded
PubMed: 37438951
DOI: 10.1002/em.22564 -
Experimental Cell Research Aug 2021DNA damage is a constant stressor to the cell. Persistent damage to the DNA over time results in an increased risk of mutation and an accumulation of mutations with age.... (Review)
Review
DNA damage is a constant stressor to the cell. Persistent damage to the DNA over time results in an increased risk of mutation and an accumulation of mutations with age. Loss of efficient DNA damage repair can lead to accelerated ageing phenotypes or an increased cancer risk, and the trade-off between cancer susceptibility and longevity is often driven by the cell's response to DNA damage. High levels of mutations in DNA repair mutants often leads to excessive cell death and stem cell exhaustion which may promote premature ageing. Stem cells themselves have distinct characteristics that enable them to retain low mutation rates. However, when mutations do arise, stem cell clonal expansion can also contribute to age-related tissue dysfunction as well as heightened cancer risk. In this review, we will highlight increasing DNA damage and mutation accumulation as hallmarks common to both ageing and cancer. We will propose that anti-ageing interventions might be cancer preventative and discuss the mechanisms through which they may act.
Topics: Aging; DNA Damage; DNA Repair; Genomic Instability; Longevity; Neoplasms
PubMed: 34102225
DOI: 10.1016/j.yexcr.2021.112679 -
International Journal of Molecular... Jun 2018
Topics: Animals; DNA Damage; DNA Repair; Humans; Mutagenesis; Neoplasms
PubMed: 29899224
DOI: 10.3390/ijms19061767 -
International Journal of Biological... 2023Liquid‒liquid phase separation (LLPS) is a phenomenon driven by weak interactions between biomolecules, such as proteins and nucleic acids, that leads to the formation... (Review)
Review
Liquid‒liquid phase separation (LLPS) is a phenomenon driven by weak interactions between biomolecules, such as proteins and nucleic acids, that leads to the formation of distinct liquid-like condensates. Through LLPS, membraneless condensates are formed, selectively concentrating specific proteins while excluding other molecules to maintain normal cellular functions. Emerging evidence shows that cancer-related mutations cause aberrant condensate assembly, resulting in disrupted signal transduction, impaired DNA repair, and abnormal chromatin organization and eventually contributing to tumorigenesis. The objective of this review is to summarize recent advancements in understanding the potential implications of LLPS in the contexts of cancer progression and therapeutic interventions. By interfering with LLPS, it may be possible to restore normal cellular processes and inhibit tumor progression. The underlying mechanisms and potential drug targets associated with LLPS in cancer are discussed, shedding light on promising opportunities for novel therapeutic interventions.
Topics: Humans; Carcinogenesis; Cell Transformation, Neoplastic; DNA Repair; Drug Delivery Systems; Mutation
PubMed: 37705755
DOI: 10.7150/ijbs.81521 -
Cancer Discovery Jul 2017DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a... (Review)
Review
DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies. Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies.
Topics: Antineoplastic Agents; Biomarkers, Tumor; DNA Damage; DNA Repair; Genomic Instability; Humans; Immunotherapy; Neoplasms
PubMed: 28630051
DOI: 10.1158/2159-8290.CD-17-0226 -
Genes Jun 2023Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...].
Cells are constantly assaulted by endogenous and exogenous sources of DNA damage that threaten genome stability [...].
Topics: Humans; DNA Repair; DNA Damage; Genomic Instability
PubMed: 37510290
DOI: 10.3390/genes14071385 -
International Journal of Biological... 2017One of the DNA repair machineries is activated by Poly (ADP-ribose) Polymerase (PARP) enzyme. Particularly, this enzyme is involved in repair of damages to single-strand... (Review)
Review
One of the DNA repair machineries is activated by Poly (ADP-ribose) Polymerase (PARP) enzyme. Particularly, this enzyme is involved in repair of damages to single-strand DNA, thus decreasing the chances of generating double-strand breaks in the genome. Therefore, the concept to block PARP enzymes by PARP inhibitor (PARPi) was appreciated in cancer treatment. PARPi has been designed and tested for many years and became a potential supplement for the conventional chemotherapy. However, increasing evidence indicates the appearance of the resistance to this treatment. Specifically, cancer cells may acquire new mutations or events that overcome the positive effect of these drugs. This paper describes several molecular mechanisms of PARPi resistance which were reported most recently, and summarizes some strategies to reverse this type of drug resistance.
Topics: Animals; BRCA1 Protein; DNA Repair; Drug Resistance, Neoplasm; Humans; MicroRNAs; Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 28255272
DOI: 10.7150/ijbs.17240 -
Cell Death & Disease Nov 2023DNA double-strand breaks (DSBs) are the fatal type of DNA damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs are mainly repaired... (Review)
Review
DNA double-strand breaks (DSBs) are the fatal type of DNA damage mostly induced by exposure genome to ionizing radiation or genotoxic chemicals. DSBs are mainly repaired by homologous recombination (HR) and nonhomologous end joining (NHEJ). To repair DSBs, a large amount of DNA repair factors was observed to be concentrated at the end of DSBs in a specific spatiotemporal manner to form a repair center. Recently, this repair center was characterized as a condensate derived from liquid-liquid phase separation (LLPS) of key DSBs repair factors. LLPS has been found to be the mechanism of membraneless organelles formation and plays key roles in a variety of biological processes. In this review, the recent advances and mechanisms of LLPS in the formation of DSBs repair-related condensates are summarized.
Topics: DNA Breaks, Double-Stranded; DNA Repair; DNA End-Joining Repair; DNA Damage; DNA
PubMed: 37968256
DOI: 10.1038/s41419-023-06267-0