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Environmental and Molecular Mutagenesis Aug 2020Many environmental carcinogens cause DNA damage, which can result in mutations and other alterations in genomic DNA if not repaired promptly. Because of the bulkiness of... (Review)
Review
Many environmental carcinogens cause DNA damage, which can result in mutations and other alterations in genomic DNA if not repaired promptly. Because of the bulkiness of the lesions, DNA-protein crosslinks (DPCs) are one of the types of toxic DNA damage with potentially deleterious consequences. Despite the importance of DPCs, how cells remove these complex DNA adducts has been incompletely understood. However, major progress in the DPC repair field over the past 5 years now supports the view that cells are equipped with multiple mechanisms to cope with DPCs. Here, we first provide an overview of environmental substances that induce DPCs, describing the sources of exposure and mechanisms of DPC formation. We then review current models of DPC repair and discuss their significance for environmental carcinogens.
Topics: Animals; DNA; DNA Repair; DNA-Binding Proteins; Environmental Exposure; Humans
PubMed: 32329115
DOI: 10.1002/em.22381 -
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 -
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 -
Nature Reviews. Cancer Jan 2016The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in... (Review)
Review
The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy.
Topics: Animals; DNA Repair; Genetic Research; Genomic Instability; History, 20th Century; Humans; Neoplasms
PubMed: 26667849
DOI: 10.1038/nrc.2015.4 -
Mutation Research. Genetic Toxicology... Jan 2022DNA double strand breaks (DSBs) are the most threatening type of DNA lesions and must be repaired properly in order to inhibit severe diseases and cell death. There are... (Review)
Review
DNA double strand breaks (DSBs) are the most threatening type of DNA lesions and must be repaired properly in order to inhibit severe diseases and cell death. There are four major repair pathways for DSBs: non-homologous end joining (NHEJ), homologous recombination (HR), single strand annealing (SSA) and alternative end joining (alt-EJ). Cells choose repair pathway depending on the cell cycle phase and the length of 3' end of the DNA when DSBs are generated. Blunt and short regions of the 5' or 3' overhang DNA are repaired by NHEJ, which uses direct ligation or limited resection processing of the broken DNA end. In contrast, HR, SSA and alt-EJ use the resected DNA generated by the MRN (MRE11-RAD50-NBS1) complex and C-terminal binding protein interacting protein (CtIP) activated during the S and G2 phases. Here, we review recent findings on each repair pathway and the choice of repair mechanism and highlight the role of mismatch repair (MMR) protein in HR.
Topics: DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; G2 Phase; S Phase
PubMed: 35094810
DOI: 10.1016/j.mrgentox.2021.503438 -
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 -
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 -
International Journal of Molecular... May 2023DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly...
DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that the PD-associated protein DJ-1 plays an essential role in modulating DNA double-strand break (DSB) repair. Specifically, DJ-1 is a DNA damage response (DDR) protein that can be recruited to DNA damage sites, where it promotes DSB repair through both homologous recombination and nonhomologous end joining. Mechanistically, DJ-1 interacts directly with PARP1, a nuclear enzyme essential for genomic stability, and stimulates its enzymatic activity during DNA repair. Importantly, cells from PD patients with the DJ-1 mutation also have defective PARP1 activity and impaired repair of DSBs. In summary, our findings uncover a novel function of nuclear DJ-1 in DNA repair and genome stability maintenance, and suggest that defective DNA repair may contribute to the pathogenesis of PD linked to DJ-1 mutations.
Topics: Humans; DNA Breaks, Double-Stranded; DNA Repair; DNA End-Joining Repair; DNA Damage; Mutation; Genomic Instability; Poly (ADP-Ribose) Polymerase-1
PubMed: 37239999
DOI: 10.3390/ijms24108651