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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 -
Trends in Cell Biology Jan 2016DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including genomic... (Review)
Review
DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including genomic instability and cell death. Indeed, misrepair of DSBs can lead to inappropriate end-joining events, which commonly underlie oncogenic transformation due to chromosomal translocations. Typically, cells employ two main mechanisms to repair DSBs: homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). In addition, alternative error-prone DSB repair pathways, namely alternative end joining (alt-EJ) and single-strand annealing (SSA), have been recently shown to operate in many different conditions and to contribute to genome rearrangements and oncogenic transformation. Here, we review the mechanisms regulating DSB repair pathway choice, together with the potential interconnections between HR and the annealing-dependent error-prone DSB repair pathways.
Topics: Animals; Cell Survival; DNA Breaks, Double-Stranded; DNA Repair; Genomic Instability; Humans; Mutation
PubMed: 26437586
DOI: 10.1016/j.tcb.2015.07.009 -
Molecular Cell Nov 2015An underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by... (Review)
Review
An underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by radiotherapy and DNA-damaging chemotherapy is based on this principle, yet it is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions. The recent approval of olaparib (Lynparza), the poly (ADP-ribose) polymerase (PARP) inhibitor for treating tumors harboring BRCA1 or BRCA2 mutations, represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles' heel. This review highlights the different concepts behind targeting DDR in cancer and how this can provide significant opportunities for DDR-based therapies in the future.
Topics: Animals; Antineoplastic Agents; DNA Damage; DNA Repair; Genomic Instability; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 26590714
DOI: 10.1016/j.molcel.2015.10.040 -
Nature Reviews. Molecular Cell Biology Nov 2019The major pathways of DNA double-strand break (DSB) repair are crucial for maintaining genomic stability. However, if deployed in an inappropriate cellular context,... (Review)
Review
The major pathways of DNA double-strand break (DSB) repair are crucial for maintaining genomic stability. However, if deployed in an inappropriate cellular context, these same repair functions can mediate chromosome rearrangements that underlie various human diseases, ranging from developmental disorders to cancer. The two major mechanisms of DSB repair in mammalian cells are non-homologous end joining (NHEJ) and homologous recombination. In this Review, we consider DSB repair-pathway choice in somatic mammalian cells as a series of 'decision trees', and explore how defective pathway choice can lead to genomic instability. Stalled, collapsed or broken DNA replication forks present a distinctive challenge to the DSB repair system. Emerging evidence suggests that the 'rules' governing repair-pathway choice at stalled replication forks differ from those at replication-independent DSBs.
Topics: Animals; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Replication; Genomic Instability; Humans
PubMed: 31263220
DOI: 10.1038/s41580-019-0152-0 -
Annual Review of Genetics Nov 2020Accurate DNA repair and replication are critical for genomic stability and cancer prevention. and its gene family are key regulators of DNA fidelity through diverse... (Review)
Review
Accurate DNA repair and replication are critical for genomic stability and cancer prevention. and its gene family are key regulators of DNA fidelity through diverse roles in double-strand break repair, replication stress, and meiosis. RAD51 is an ATPase that forms a nucleoprotein filament on single-stranded DNA. RAD51 has the function of finding and invading homologous DNA sequences to enable accurate and timely DNA repair. Its paralogs, which arose from ancient gene duplications of , have evolved to regulate and promote RAD51 function. Underscoring its importance, misregulation of RAD51, and its paralogs, is associated with diseases such as cancer and Fanconi anemia. In this review, we focus on the mammalian RAD51 structure and function and highlight the use of model systems to enable mechanistic understanding of RAD51 cellular roles. We also discuss how misregulation of the gene family members contributes to disease and consider new approaches to pharmacologically inhibit RAD51.
Topics: Animals; DNA; DNA Repair; Genomic Instability; Homologous Recombination; Humans; Rad51 Recombinase
PubMed: 32663049
DOI: 10.1146/annurev-genet-021920-092410 -
Seminars in Cancer Biology Nov 2021Genomic instability consists of a range of genetic alterations within the genome that contributes to tumor heterogeneity and drug resistance. It is a well-established... (Review)
Review
Genomic instability consists of a range of genetic alterations within the genome that contributes to tumor heterogeneity and drug resistance. It is a well-established characteristic of most cancer cells. Genome instability induction results from defects in DNA damage surveillance mechanisms, mitotic checkpoints and DNA repair machinery. Accumulation of genetic alterations ultimately sets cells towards malignant transformation. Recent studies suggest that miRNAs are key players in mediating genome instability. miRNAs are a class of small RNAs expressed in most somatic tissues and are part of the epigenome. Importantly, in many cancers, miRNA expression is dysregulated. Consequently, this review examines the role of miRNA dysregulation as a causal step for induction of genome instability and subsequent carcinogenesis. We focus specifically on mechanistic studies assessing miRNA(s) and specific subtypes of genome instability or known modes of genome instability. In addition, we provide insight on the existing knowledge gaps within the field and possible ways to address them.
Topics: Animals; Carcinogenesis; DNA Repair; Genomic Instability; Humans; MicroRNAs; Neoplasms
PubMed: 33979676
DOI: 10.1016/j.semcancer.2021.05.004 -
Nature Reviews. Molecular Cell Biology Aug 2017Genome duplication is carried out by pairs of replication forks that assemble at origins of replication and then move in opposite directions. DNA replication ends when... (Review)
Review
Genome duplication is carried out by pairs of replication forks that assemble at origins of replication and then move in opposite directions. DNA replication ends when converging replication forks meet. During this process, which is known as replication termination, DNA synthesis is completed, the replication machinery is disassembled and daughter molecules are resolved. In this Review, we outline the steps that are likely to be common to replication termination in most organisms, namely, fork convergence, synthesis completion, replisome disassembly and decatenation. We briefly review the mechanism of termination in the bacterium Escherichia coli and in simian virus 40 (SV40) and also focus on recent advances in eukaryotic replication termination. In particular, we discuss the recently discovered E3 ubiquitin ligases that control replisome disassembly in yeast and higher eukaryotes, and how their activity is regulated to avoid genome instability.
Topics: DNA; DNA Replication; Escherichia coli; Genomic Instability; Saccharomyces cerevisiae
PubMed: 28537574
DOI: 10.1038/nrm.2017.42 -
Aging Cell Feb 2020The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are... (Review)
Review
The global population of individuals over the age of 65 is growing at an unprecedented rate and is expected to reach 1.6 billion by 2050. Most older individuals are affected by multiple chronic diseases, leading to complex drug treatments and increased risk of physical and cognitive disability. Improving or preserving the health and quality of life of these individuals is challenging due to a lack of well-established clinical guidelines. Physicians are often forced to engage in cycles of "trial and error" that are centered on palliative treatment of symptoms rather than the root cause, often resulting in dubious outcomes. Recently, geroscience challenged this view, proposing that the underlying biological mechanisms of aging are central to the global increase in susceptibility to disease and disability that occurs with aging. In fact, strong correlations have recently been revealed between health dimensions and phenotypes that are typical of aging, especially with autophagy, mitochondrial function, cellular senescence, and DNA methylation. Current research focuses on measuring the pace of aging to identify individuals who are "aging faster" to test and develop interventions that could prevent or delay the progression of multimorbidity and disability with aging. Understanding how the underlying biological mechanisms of aging connect to and impact longitudinal changes in health trajectories offers a unique opportunity to identify resilience mechanisms, their dynamic changes, and their impact on stress responses. Harnessing how to evoke and control resilience mechanisms in individuals with successful aging could lead to writing a new chapter in human medicine.
Topics: Aging; Animals; Cellular Senescence; Epigenesis, Genetic; Genomic Instability; Geriatrics; Humans; Inflammation; Mitochondria; Morbidity; Proteostasis; Reactive Oxygen Species; Stem Cells; Telomere Homeostasis
PubMed: 31833194
DOI: 10.1111/acel.13080 -
Cancer Science May 2020DNA double-strand break (DSB) is a serious type of DNA damage and is known to trigger multiple responses within cells. In these responses, novel relationships among DSB,... (Review)
Review
DNA double-strand break (DSB) is a serious type of DNA damage and is known to trigger multiple responses within cells. In these responses, novel relationships among DSB, DSB repair, and transcription machineries are created. First, transcription is repressed if DSB occurs near or at the transcription site, termed DSB-induced transcriptional repression, which contributes to DSB repair with the aid of DNA damage-signaling pathways, ATM- or DNA-PKcs-signaling pathways. DSB-induced transcriptional repression is also regulated by transcriptional factors TLP1, NELF, and ENL, as well as chromatin remodeling and organizing factors ZMYND8, CDYL1, PBAF, and cohesin. Second, transcription and RNA promote DSB repair for genome integrity. Transcription factors such as LEDGF, SETD2, and transcriptionally active histone modification, H3K36, facilitate homologous recombination to overcome DSB. At transcriptional active sites, DNA:RNA hybrids, termed R-loops, which are formed by DSB, are processed by RAD52 and XPG leading to an activation of the homologous recombination pathway. Even in a transcriptionally inactive non-genic sites, noncoding RNAs that are produced by RNA polymerase II, DICER, and DROSHA, help to recruit DSB repair proteins at the DSB sites. Third, transcriptional activation itself, however, can induce DSB. Transcriptional activation often generates specific DNA structures such as R-loops and topoisomerase-induced DSBs, which cause genotoxic stress and may lead to genome instability and consequently to cancer. Thus, transcription and DSB repair machineries interact and cooperate to prevent genome instability and cancer.
Topics: DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Genomic Instability; Homologous Recombination; Humans; Neoplasms; RNA; Transcription, Genetic; Transcriptional Activation
PubMed: 32232911
DOI: 10.1111/cas.14404 -
Developmental Cell Sep 2021Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of...
Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed.
Topics: Aneuploidy; Chromosomal Instability; Drug Resistance; Drug Therapy; Gene Dosage; Genomic Instability; Humans; Karyotype
PubMed: 34352223
DOI: 10.1016/j.devcel.2021.07.006