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Biomolecules Sep 2015The maintenance of genomic integrity is an important process in organisms as failure to sense and repair damaged DNA can result in a variety of diseases. Eukaryotic... (Review)
Review
The maintenance of genomic integrity is an important process in organisms as failure to sense and repair damaged DNA can result in a variety of diseases. Eukaryotic cells have developed complex DNA repair response (DDR) mechanisms to accurately sense and repair damaged DNA. Post-translational modifications by ubiquitin and ubiquitin-like proteins, such as SUMO and NEDD8, have roles in coordinating the progression of DDR. Proteins in the neddylation pathway have also been linked to regulating DDR. Of interest is the COP9 signalosome (CSN), a multi-subunit metalloprotease present in eukaryotes that removes NEDD8 from cullins and regulates the activity of cullin-RING ubiquitin ligases (CRLs). This in turn regulates the stability and turnover of a host of CRL-targeted proteins, some of which have established roles in DDR. This review will summarize the current knowledge on the role of the CSN and neddylation in DNA repair.
Topics: Animals; COP9 Signalosome Complex; DNA Damage; DNA Repair; Humans; Multiprotein Complexes; Peptide Hydrolases; Protein Processing, Post-Translational; Ubiquitin; Ubiquitination
PubMed: 26437438
DOI: 10.3390/biom5042388 -
Genes Feb 2022Double-strand breaks (DSBs) are considered to be one of the most harmful and mutagenic forms of DNA damage. They are highly toxic if unrepaired, and can cause genome... (Review)
Review
Double-strand breaks (DSBs) are considered to be one of the most harmful and mutagenic forms of DNA damage. They are highly toxic if unrepaired, and can cause genome rearrangements and even cell death. Cells employ two major pathways to repair DSBs: homologous recombination (HR) and non-homologous end-joining (NHEJ). In plants, most applications of genome modification techniques depend on the development of DSB repair pathways, such as -mediated transformation (AMT) and gene targeting (GT). In this paper, we review the achieved knowledge and recent advances on the DNA DSB response and its main repair pathways; discuss how these pathways affect -mediated T-DNA integration and gene targeting in plants; and describe promising strategies for producing DSBs artificially, at definite sites in the genome.
Topics: DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; DNA, Plant; Homologous Recombination
PubMed: 35205367
DOI: 10.3390/genes13020322 -
FEMS Microbiology Reviews Jul 2018There has long been a fascination in the DNA repair pathways of archaea, for two main reasons. Firstly, many archaea inhabit extreme environments where the rate of... (Review)
Review
There has long been a fascination in the DNA repair pathways of archaea, for two main reasons. Firstly, many archaea inhabit extreme environments where the rate of physical damage to DNA is accelerated. These archaea might reasonably be expected to have particularly robust or novel DNA repair pathways to cope with this. Secondly, the archaea have long been understood to be a lineage distinct from the bacteria, and to share a close relationship with the eukarya, particularly in their information processing systems. Recent discoveries suggest the eukarya arose from within the archaeal domain, and in particular from lineages related to the TACK superphylum and Lokiarchaea. Thus, archaeal DNA repair proteins and pathways can represent a useful model system. This review focuses on recent advances in our understanding of archaeal DNA repair processes including base excision repair, nucleotide excision repair, mismatch repair and double-strand break repair. These advances are discussed in the context of the emerging picture of the evolution and relationship of the three domains of life.
Topics: Archaea; Biological Evolution; DNA Repair; DNA, Archaeal
PubMed: 29741625
DOI: 10.1093/femsre/fuy020 -
Journal of Radiation Research Jan 2009Base moieties in DNA are spontaneously threatened by naturally occurring chemical reactions such as deamination, hydrolysis and oxidation. These DNA modifications have... (Review)
Review
Base moieties in DNA are spontaneously threatened by naturally occurring chemical reactions such as deamination, hydrolysis and oxidation. These DNA modifications have been considered to be major causes of cell death, mutations and cancer induction in organisms. Organisms have developed the DNA base excision repair pathway as a defense mechanism to protect them from these threats. DNA glycosylases, the key enzyme in the base excision repair pathway, are highly conserved in evolution. Uracil constantly occurs in DNA. Uracil in DNA arises by spontaneous deamination of cytosine to generate pro-mutagenic U:G mispairs. Uracil in DNA is also produced by the incorporation of dUMP during DNA replication. Uracil-DNA glycosylase (UNG) acts as a major repair enzyme that protects DNA from the deleterious consequences of uracil. The first UNG activity was discovered in E. coli in 1974. This was also the first discovery of base excision repair. The sequence encoded by the ung gene demonstrates that the E. coli UNG is highly conserved in viruses, bacteria, archaea, yeast, mice and humans. In this review, we will focus on central and recent findings on the generation, biological consequences and repair mechanisms of uracil in DNA and on the biological significance of uracil-DNA glycosylase.
Topics: Animals; Arabinofuranosyluracil; Computer Simulation; DNA Damage; DNA Repair; Humans; Models, Biological; Uracil-DNA Glycosidase
PubMed: 18987436
DOI: 10.1269/jrr.08080 -
Nucleic Acids Research Dec 2016Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and... (Review)
Review
Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair. Furthermore, we discuss possible mechanisms whereby these histone/protein deacetylases facilitate the switch between DNA double-strand break (DSB) repair pathways, how SIRTs play a central role in the crosstalk between DNA repair and cell death pathways due to their dependence on NAD, and the influence of small molecule HDAC inhibitors (HDACi) on cancer cell resistance to genotoxin based therapies. Throughout the review, we endeavor to identify the specific HDAC targeted by HDACi leading to therapy sensitization.
Topics: Animals; DNA Breaks, Double-Stranded; DNA Damage; DNA End-Joining Repair; DNA Repair; Histone Deacetylase Inhibitors; Histone Deacetylases; Homologous Recombination; Humans; Neoplasms; Signal Transduction; Sirtuins
PubMed: 27738139
DOI: 10.1093/nar/gkw922 -
Journal of Bacteriology Jul 2017In bacteria, replication forks assembled at a replication origin travel to the terminus, often a few megabases away. They may encounter obstacles that trigger replisome... (Review)
Review
In bacteria, replication forks assembled at a replication origin travel to the terminus, often a few megabases away. They may encounter obstacles that trigger replisome disassembly, rendering replication restart from abandoned forks crucial for cell viability. During the past 25 years, the genes that encode replication restart proteins have been identified and genetically characterized. In parallel, the enzymes were purified and analyzed , where they can catalyze replication initiation in a sequence-independent manner from fork-like DNA structures. This work also revealed a close link between replication and homologous recombination, as replication restart from recombination intermediates is an essential step of DNA double-strand break repair in bacteria and, conversely, arrested replication forks can be acted upon by recombination proteins and converted into various recombination substrates. In this review, we summarize this intense period of research that led to the characterization of the ubiquitous replication restart protein PriA and its partners, to the definition of several replication restart pathways , and to the description of tight links between replication and homologous recombination, responsible for the importance of replication restart in the maintenance of genome stability.
Topics: Bacteria; DNA Repair; DNA Replication; DNA, Bacterial; Mutation
PubMed: 28320884
DOI: 10.1128/JB.00102-17 -
Trends in Genetics : TIG Dec 2023Genome integrity and maintenance are essential for the viability of all organisms. A wide variety of DNA damage types have been described, but double-strand breaks... (Review)
Review
Genome integrity and maintenance are essential for the viability of all organisms. A wide variety of DNA damage types have been described, but double-strand breaks (DSBs) stand out as one of the most toxic DNA lesions. Two major pathways account for the repair of DSBs: homologous recombination (HR) and non-homologous end joining (NHEJ). Both pathways involve complex DNA transactions catalyzed by proteins that sequentially or cooperatively work to repair the damage. Single-molecule methods allow visualization of these complex transactions and characterization of the protein:DNA intermediates of DNA repair, ultimately allowing a comprehensive breakdown of the mechanisms underlying each pathway. We review current understanding of the HR and NHEJ responses to DSBs in eukaryotic cells, with a particular emphasis on recent advances through the use of single-molecule techniques.
Topics: DNA Breaks, Double-Stranded; DNA Repair; DNA; DNA Damage; DNA End-Joining Repair
PubMed: 37806853
DOI: 10.1016/j.tig.2023.09.004 -
Clinical Cancer Research : An Official... Aug 2009Epigenetic silencing of essential components of DNA repair pathways is a common event in many tumor types, and comprise O6-methylguanine-DNA methyltransferase (MGMT),... (Review)
Review
Epigenetic silencing of essential components of DNA repair pathways is a common event in many tumor types, and comprise O6-methylguanine-DNA methyltransferase (MGMT), human mut L homolog 1 (hMLH1), Werner syndrome gene (WRN), breast cancer susceptibility gene 1 (BRCA1), and genes of the Fanconi anemia pathway. Most interestingly, some of these alterations become the Achilles heel of the affected tumors upon treatment with certain classes of anticancer agents. That is, patients whose tumors carry such defects can be stratified for respective therapy rendering some classic DNA damaging agents, such as alkylators or DNA crosslinking agents, into "targeted therapies." Here we review some of the affected repair pathways that, when inactivated, sensitize the tumors to specific drugs and are thus exploitable for individualized therapy.
Topics: Antineoplastic Agents; DNA Repair; Drug Delivery Systems; Epigenesis, Genetic; Humans; Models, Biological; Neoplasms; Signal Transduction
PubMed: 19671858
DOI: 10.1158/1078-0432.CCR-08-1169 -
Genes Oct 2022In response to DNA double strand breaks (DSB), repair proteins accumulate at damaged sites, forming membrane-less condensates or "foci". The formation of these foci and... (Review)
Review
In response to DNA double strand breaks (DSB), repair proteins accumulate at damaged sites, forming membrane-less condensates or "foci". The formation of these foci and their disassembly within the proper time window are essential for genome integrity. However, how these membrane-less sub-compartments are formed, maintained and disassembled remains unclear. Recently, several studies across different model organisms proposed that DNA repair foci form via liquid phase separation. In this review, we discuss the current research investigating the physical nature of repair foci. First, we present the different models of condensates proposed in the literature, highlighting the criteria to differentiate them. Second, we discuss evidence of liquid phase separation at DNA repair sites and the limitations of this model to fully describe structures formed in response to DNA damage. Finally, we discuss the origin and possible function of liquid phase separation for DNA repair processes.
Topics: DNA-Binding Proteins; DNA Breaks, Double-Stranded; DNA Repair; DNA Damage; DNA
PubMed: 36292731
DOI: 10.3390/genes13101846 -
Nature Communications May 2020Cells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically...
Cells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.
Topics: Animals; Caenorhabditis elegans; DNA Damage; DNA Repair; Genomics; Humans; Mutation; Point Mutation
PubMed: 32358516
DOI: 10.1038/s41467-020-15912-7