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Environmental and Molecular Mutagenesis Aug 2020Environmental DNA damaging agents continuously challenge the integrity of the genome by introducing a variety of DNA lesions. The DNA damage caused by environmental... (Review)
Review
Environmental DNA damaging agents continuously challenge the integrity of the genome by introducing a variety of DNA lesions. The DNA damage caused by environmental factors will lead to mutagenesis and subsequent carcinogenesis if they are not removed efficiently by repair pathways. Methods for detection of DNA damage and repair can be applied to identify, visualize, and quantify the DNA damage formation and repair events, and they enable us to illustrate the molecular mechanisms of DNA damage formation, DNA repair pathways, mutagenesis, and carcinogenesis. Ever since the discovery of the double helical structure of DNA in 1953, a great number of methods have been developed to detect various types of DNA damage and repair. Rapid advances in sequencing technologies have facilitated the emergence of a variety of novel methods for detecting environmentally induced DNA damage and repair at the genome-wide scale during the last decade. In this review, we provide a historical overview of the development of various damage detection methods. We also highlight the current methodologies to detect DNA damage and repair, especially some next generation sequencing-based methods.
Topics: Animals; Carcinogenesis; DNA; DNA Damage; DNA Repair; Environmental Exposure; High-Throughput Nucleotide Sequencing; Humans; Mutagenesis
PubMed: 32083352
DOI: 10.1002/em.22365 -
Seminars in Cell & Developmental Biology May 2021Human CtIP was originally identified as an interactor of the retinoblastoma protein and BRCA1, two bona fide tumour suppressors frequently mutated in cancer. CtIP is... (Review)
Review
Human CtIP was originally identified as an interactor of the retinoblastoma protein and BRCA1, two bona fide tumour suppressors frequently mutated in cancer. CtIP is renowned for its role in the resection of DNA double-strand breaks (DSBs) during homologous recombination, a largely error-free DNA repair pathway crucial in maintaining genome integrity. However, CtIP-dependent DNA end resection is equally accountable for alternative end-joining, a mutagenic DSB repair mechanism implicated in oncogenic chromosomal translocations. In addition, CtIP contributes to transcriptional regulation of G1/S transition, DNA damage checkpoint signalling, and replication fork protection pathways. In this review, we present a perspective on the current state of knowledge regarding the tumour-suppressive and oncogenic properties of CtIP and provide an overview of their relevance for cancer development, progression, and therapy.
Topics: Carcinogenesis; DNA Repair; Humans
PubMed: 32950401
DOI: 10.1016/j.semcdb.2020.09.001 -
Trends in Biochemical Sciences Apr 2015Sumoylation has important roles during DNA damage repair and responses. Recent broad-scope and substrate-based studies have shed light on the regulation and significance... (Review)
Review
Sumoylation has important roles during DNA damage repair and responses. Recent broad-scope and substrate-based studies have shed light on the regulation and significance of sumoylation during these processes. An emerging paradigm is that sumoylation of many DNA metabolism proteins is controlled by DNA engagement. Such 'on-site modification' can explain low substrate modification levels and has important implications in sumoylation mechanisms and effects. New studies also suggest that sumoylation can regulate a process through an ensemble effect or via major substrates. Additionally, we describe new trends in the functional effects of sumoylation, such as bi-directional changes in biomolecule binding and multilevel coordination with other modifications. These emerging themes and models will stimulate our thinking and research in sumoylation and genome maintenance.
Topics: Animals; DNA Repair; Humans; Protein Processing, Post-Translational; SUMO-1 Protein; Sumoylation
PubMed: 25778614
DOI: 10.1016/j.tibs.2015.02.006 -
Biochemical Pharmacology Sep 2019Mitosis ensures accurate segregation of duplicated DNA through tight regulation of chromosome condensation, bipolar spindle assembly, chromosome alignment in the... (Review)
Review
Mitosis ensures accurate segregation of duplicated DNA through tight regulation of chromosome condensation, bipolar spindle assembly, chromosome alignment in the metaphase plate, chromosome segregation and cytokinesis. Poly(ADP-ribose) polymerases (PARPs), in particular PARP1, PARP2, PARP3, PARP5a (TNKS1), as well as poly(ADP-ribose) glycohydrolase (PARG), regulate different mitotic functions, including centrosome function, mitotic spindle assembly, mitotic checkpoints, telomere length and telomere cohesion. PARP depletion or inhibition give rise to various mitotic defects such as centrosome amplification, multipolar spindles, chromosome misalignment, premature loss of cohesion, metaphase arrest, anaphase DNA bridges, lagging chromosomes, and micronuclei. As the mechanisms of PARP1/2 inhibitor-mediated cell death are being progressively elucidated, it is becoming clear that mitotic defects caused by PARP1/2 inhibition arise due to replication stress and DNA damage in S phase. As it stands, entrapment of inactive PARP1/2 on DNA phenocopies replication stress through accumulation of unresolved replication intermediates, double-stranded DNA breaks (DSBs) and incorrectly repaired DSBs, which can be transmitted from S phase to mitosis and instigate various mitotic defects, giving rise to both numerical and structural chromosomal aberrations. Cancer cells have increased levels of replication stress, which makes them particularly susceptible to a combination of agents that compromise replication fork stability. Indeed, combining PARP1/2 inhibitors with genetic deficiencies in DNA repair pathways, DNA-damaging agents, ATR and other cell cycle checkpoint inhibitors has yielded synergistic effects in killing cancer cells. Here I provide a comprehensive overview of the mitotic functions of PARPs and PARG, mitotic phenotypes induced by their depletion or inhibition, as well as the therapeutic relevance of targeting mitotic cells by directly interfering with mitotic functions or indirectly through replication stress.
Topics: Animals; DNA Damage; DNA Repair; Humans; Mitosis; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 30910692
DOI: 10.1016/j.bcp.2019.03.028 -
Chemical Research in Toxicology Jan 2023Recognition and repair of DNA lesions are critical for cell survival. Herein, we highlight recent advances in the sequencing, repair mechanisms, and biological...
Recognition and repair of DNA lesions are critical for cell survival. Herein, we highlight recent advances in the sequencing, repair mechanisms, and biological consequences of DNA lesions presented at the 2022 Fall American Chemical Society meeting.
Topics: DNA Repair; DNA Damage; DNA
PubMed: 36580364
DOI: 10.1021/acs.chemrestox.2c00307 -
Clinical Oncology (Royal College of... May 2019It has been well established that an accumulation of mutations in DNA, whether caused by external sources (e.g. ultraviolet light, radioactivity) or internal sources... (Review)
Review
It has been well established that an accumulation of mutations in DNA, whether caused by external sources (e.g. ultraviolet light, radioactivity) or internal sources (e.g. metabolic by-products, such as reactive oxygen species), has the potential to cause a cell to undergo carcinogenesis and increase the risk for the development of cancer. Therefore, it is critically important for a cell to have the capacity to properly respond to and repair DNA damage as it occurs. The DNA damage response (DDR) describes a collection of DNA repair pathways that aid in the protection of genomic integrity by detecting myriad types of DNA damage and initiating the correct DNA repair pathway. In many instances, a deficiency in the DDR, whether inherited or spontaneously assumed, can increase the risk of carcinogenesis and ultimately tumorigenesis through the accumulation of mutations that fail to be properly repaired. Interestingly, although disruption of the DDR can lead to the initial genomic instability that can ultimately cause carcinogenesis, the DDR has also proven to be an invaluable target for anticancer drugs and therapies. Making matters more complicated, the DDR is also involved in the resistance to first-line cancer therapy. In this review, we will consider therapies already in use in the clinic and ongoing research into other avenues of treatment that target DNA repair pathways in cancer.
Topics: DNA Repair; Humans; Neoplasms
PubMed: 30876709
DOI: 10.1016/j.clon.2019.02.007 -
Experimental Gerontology Aug 2010Mitochondrial DNA is constantly exposed to oxidative injury. Due to its location close to the main site of reactive oxygen species, the inner mitochondrial membrane,... (Review)
Review
Mitochondrial DNA is constantly exposed to oxidative injury. Due to its location close to the main site of reactive oxygen species, the inner mitochondrial membrane, mtDNA is more susceptible than nuclear DNA to oxidative damage. The accumulation of DNA damage is thought to play a critical role in the aging process and to be particularly deleterious in post-mitotic cells. Thus, DNA repair is an important mechanism for maintenance of genomic integrity. Despite the importance of mitochondria in the aging process, it was thought for many years that mitochondria lacked an enzymatic DNA repair system comparable to that in the nuclear compartment. However, it is now well established that DNA repair actively takes place in mitochondria. Oxidative DNA damage processing, base excision repair mechanisms were the first to be described in these organelles, and consequently the best understood. However, new proteins and novel DNA repair pathways, thought to be exclusively present in the nucleus, have recently been described also to be present in mitochondria. Here we review the main mitochondrial DNA repair pathways and their association with the aging process.
Topics: Aging; Animals; DNA Damage; DNA Glycosylases; DNA Ligases; DNA Mismatch Repair; DNA Repair; DNA, Mitochondrial; DNA-(Apurinic or Apyrimidinic Site) Lyase; DNA-Directed DNA Polymerase; Humans; Mitochondria; Models, Biological; Reactive Oxygen Species
PubMed: 20096766
DOI: 10.1016/j.exger.2010.01.017 -
Nature Communications Sep 2022DNA double-strand breaks (DSB) are repaired by multiple distinct pathways, with outcomes ranging from error-free repair to mutagenesis and genomic loss. DSB-repair...
DNA double-strand breaks (DSB) are repaired by multiple distinct pathways, with outcomes ranging from error-free repair to mutagenesis and genomic loss. DSB-repair pathway cross-talk and compensation is incompletely understood, despite its importance for genomic stability, oncogenesis, and genome editing using CRISPR/Cas9. To address this, we constructed and validated three fluorescent Cas9-based reporters, named DSB-Spectrum, that simultaneously quantify the contribution of multiple DNA repair pathways at a DSB. DSB-Spectrum reporters distinguish between DSB-repair by error-free canonical non-homologous end-joining (c-NHEJ) versus homologous recombination (HR; reporter 1), mutagenic repair versus HR (reporter 2), and mutagenic end-joining versus single strand annealing (SSA) versus HR (reporter 3). Using these reporters, we show that inhibiting the c-NHEJ factor DNA-PKcs increases repair by HR, but also substantially increases mutagenic SSA. Our data indicate that SSA-mediated DSB-repair also occurs at endogenous genomic loci, driven by Alu elements or homologous gene regions. Finally, we demonstrate that long-range end-resection factors DNA2 and Exo1 promote SSA and reduce HR, when both pathways compete for the same substrate. These new Cas9-based DSB-Spectrum reporters facilitate the comprehensive analysis of repair pathway crosstalk and DSB-repair outcome.
Topics: CRISPR-Cas Systems; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Homologous Recombination
PubMed: 36075911
DOI: 10.1038/s41467-022-32743-w -
Redox Biology Jan 2020Chemical modifications of DNA and RNA regulate genome functions or trigger mutagenesis resulting in aging or cancer. Oxidations of macromolecules, including DNA, are... (Review)
Review
Chemical modifications of DNA and RNA regulate genome functions or trigger mutagenesis resulting in aging or cancer. Oxidations of macromolecules, including DNA, are common reactions in biological systems and often part of regulatory circuits rather than accidental events. DNA alterations are particularly relevant since the unique role of nuclear and mitochondrial genome is coding enduring and inheritable information. Therefore, an alteration in DNA may represent a relevant problem given its transmission to daughter cells. At the same time, the regulation of gene expression allows cells to continuously adapt to the environmental changes that occur throughout the life of the organism to ultimately maintain cellular homeostasis. Here we review the multiple ways that lead to DNA oxidation and the regulation of mechanisms activated by cells to repair this damage. Moreover, we present the recent evidence suggesting that DNA damage caused by physiological metabolism acts as epigenetic signal for regulation of gene expression. In particular, the predisposition of guanine to oxidation might reflect an adaptation to improve the genome plasticity to redox changes.
Topics: DNA Damage; DNA Repair; Epigenesis, Genetic; Guanosine; Oxidation-Reduction
PubMed: 31926624
DOI: 10.1016/j.redox.2019.101398 -
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