-
Physical Chemistry Chemical Physics :... May 2015Photolyases, a class of flavoproteins, use blue light to repair two types of ultraviolet-induced DNA damage, a cyclobutane pyrimidine dimer (CPD) and a... (Review)
Review
Photolyases, a class of flavoproteins, use blue light to repair two types of ultraviolet-induced DNA damage, a cyclobutane pyrimidine dimer (CPD) and a pyrimidine-pyrimidone (6-4) photoproduct (6-4PP). In this perspective, we review the recent progress in the repair dynamics and mechanisms of both types of DNA restoration by photolyases. We first report the spectroscopic characterization of flavin in various redox states and the active-site solvation dynamics in photolyases. We then systematically summarize the detailed repair dynamics of damaged DNA by photolyases and a biomimetic system through resolving all elementary steps on ultrafast timescales, including multiple intermolecular electron- and proton-transfer reactions and bond-breaking and -making processes. We determined the unique electron tunneling pathways, identified the key functional residues and revealed the molecular origin of high repair efficiency, and thus elucidate the molecular mechanisms and repair photocycles at the most fundamental level. We finally conclude that the active sites of photolyases, unlike the aqueous solution for the biomimetic system, provide a unique electrostatic environment and local flexibility and thus a dedicated synergy for all elementary dynamics to maximize the repair efficiency. This repair photomachine is the first enzyme that the entire functional evolution is completely mapped out in real time.
Topics: Animals; Catalytic Domain; DNA; DNA Damage; DNA Repair; Deoxyribodipyrimidine Photo-Lyase; Humans; Light; Models, Molecular; Mutation; Protein Conformation; Pyrimidine Dimers; Ultraviolet Rays
PubMed: 25870862
DOI: 10.1039/c4cp05286b -
International Journal of Molecular... Sep 2017DNA damage is constantly produced by both endogenous and exogenous factors; DNA lesions then trigger the so-called DNA damaged response (DDR). This is a highly... (Review)
Review
DNA damage is constantly produced by both endogenous and exogenous factors; DNA lesions then trigger the so-called DNA damaged response (DDR). This is a highly synchronized pathway that involves recognition, signaling and repair of the damage. Failure to eliminate DNA lesions is associated with genome instability, a driving force in tumorigenesis. Proteins carry out the vast majority of cellular functions and thus proteome quality control (PQC) is critical for the maintenance of cellular functionality. PQC is assured by the proteostasis network (PN), which under conditions of proteome instability address the triage decision of protein , , or . Key components of the PN are the protein synthesis modules, the molecular chaperones and the two main degradation machineries, namely the autophagy-lysosome and the ubiquitin-proteasome pathways; also, part of the PN are a number of stress-responsive cellular sensors including (among others) heat shock factor 1 (Hsf1) and the nuclear factor erythroid 2-related factor 2 (Nrf2). Nevertheless, the lifestyle- and/or ageing-associated gradual accumulation of stressors results in increasingly damaged and unstable proteome due to accumulation of misfolded proteins and/or protein aggregates. This outcome may then increase genomic instability due to reduced fidelity in processes like DNA replication or repair leading to various age-related diseases including cancer. Herein, we review the role of proteostatic machineries in nuclear genome integrity and stability, as well as on DDR responses.
Topics: Animals; Autophagy; DNA Damage; Genomic Instability; Humans; Oxidative Stress; Proteome
PubMed: 28937603
DOI: 10.3390/ijms18102036 -
Cells Jul 2021Many anti-cancer therapeutics lead to the release of danger associated pattern molecules (DAMPs) as the result of killing large numbers of both normal and transformed... (Review)
Review
Many anti-cancer therapeutics lead to the release of danger associated pattern molecules (DAMPs) as the result of killing large numbers of both normal and transformed cells as well as lysis of red blood cells (RBC) (hemolysis). Labile heme originating from hemolysis acts as a DAMP while its breakdown products exert varying immunomodulatory effects. Labile heme is scavenged by hemopexin (Hx) and processed by heme oxygenase-1 (HO-1, ), resulting in its removal and the generation of biliverdin/bilirubin, carbon monoxide (CO) and iron. We recently demonstrated that labile heme accumulates in cancer cell nuclei in the tumor parenchyma of knockout mice and contributes to the malignant phenotype of prostate cancer (PCa) cells and increased metastases. Additionally, this work identified Hx as a tumor suppressor gene. Direct interaction of heme with DNA G-quadruplexes (G4) leads to altered gene expression in cancer cells that regulate transcription, recombination and replication. Here, we provide new data supporting the nuclear role of HO-1 and heme in modulating DNA damage response, G4 stability and cancer growth. Finally, we discuss an alternative role of labile heme as a nuclear danger signal (NDS) that regulates gene expression and nuclear HO-1 regulated DNA damage responses stimulated by its interaction with G4.
Topics: Animals; DNA Damage; G-Quadruplexes; Gene Expression; Gene Expression Regulation; Humans; Immunity; Neoplasms
PubMed: 34359970
DOI: 10.3390/cells10071801 -
Genes Nov 2021Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR... (Review)
Review
Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress in this field has been driven by model genetic organism research. This review has two main purposes. First, we provide a survey of model organism-based efforts to study DDRs. Second, we highlight how model organism study has contributed to understanding how specific DDRs are influenced by cell cycle stage. We also look forward, with a discussion of how future study can be expanded beyond typical model genetic organisms to further illuminate how the genome is protected.
Topics: Animals; Cell Cycle; Cell Cycle Checkpoints; DNA Damage; DNA Repair; Humans; Signal Transduction
PubMed: 34946831
DOI: 10.3390/genes12121882 -
Journal of Immunology Research 2018Systemic lupus erythematosus (SLE) is a perplexing and potentially severe disease, the pathogenesis of which is yet to be understood. SLE is considered to be a... (Review)
Review
Systemic lupus erythematosus (SLE) is a perplexing and potentially severe disease, the pathogenesis of which is yet to be understood. SLE is considered to be a multifactorial disease, in which genetic factors, immune dysregulation, and environmental factors, such as ultraviolet radiation, are involved. Recently, the description of novel genes conferring susceptibility to develop SLE even in their own (monogenic lupus) has raised the interest in DNA dynamics since many of these genes are linked to DNA repair. Damage to DNA induces an inflammatory response and eventually triggers an immune response, including those targeting self-antigens. We review the evidence that indicates that patients with SLE present higher levels of DNA damage than normal subjects do and that several proteins involved in the preservation of the genomic stability show polymorphisms, some of which increase the risk for SLE development. Also, the experience from animal models reinforces the connection between DNA damage and defective repair in the development of SLE-like disease including characteristic features such as anti-DNA antibodies and nephritis. Defining the role of DNA damage response in SLE pathogenesis might be strategic in the quest for novel therapies.
Topics: Animals; DNA Damage; DNA Repair; Humans; Lupus Erythematosus, Systemic
PubMed: 30116756
DOI: 10.1155/2018/8214379 -
Nature Reviews. Cancer Mar 2015The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects... (Review)
Review
The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets.
Topics: DNA Damage; DNA Repair; Humans; Neoplasms
PubMed: 25709118
DOI: 10.1038/nrc3891 -
Nature Reviews. Molecular Cell Biology Aug 2017The idea that signal-dependent transcription might involve the generation of transient DNA nicks or even breaks in the regulatory regions of genes, accompanied by... (Review)
Review
The idea that signal-dependent transcription might involve the generation of transient DNA nicks or even breaks in the regulatory regions of genes, accompanied by activation of DNA damage repair pathways, would seem to be counterintuitive, as DNA damage is usually considered harmful to cellular integrity. However, recent studies have generated a substantial body of evidence that now argues that programmed DNA single- or double-strand breaks can, at least in specific cases, have a role in transcription regulation. Here, we discuss the emerging functions of DNA breaks in the relief of DNA torsional stress and in promoter and enhancer activation.
Topics: Animals; DNA; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Gene Expression Regulation; Humans
PubMed: 28537575
DOI: 10.1038/nrm.2017.43 -
Journal of Translational Medicine Sep 2023Genomic instability is a common hallmark of human tumours. As a carrier of genetic information, DNA is constantly threatened by various damaging factors that, if not... (Review)
Review
Genomic instability is a common hallmark of human tumours. As a carrier of genetic information, DNA is constantly threatened by various damaging factors that, if not repaired in time, can affect the transmission of genetic information and lead to cellular carcinogenesis. In response to these threats, cells have evolved a range of DNA damage response mechanisms, including DNA damage repair, to maintain genomic stability. The X-ray repair cross-complementary gene family (XRCC) comprises an important class of DNA damage repair genes that encode proteins that play important roles in DNA single-strand breakage and DNA base damage repair. The dysfunction of the XRCC gene family is associated with the development of various tumours. In the context of tumours, mutations in XRCC and its aberrant expression, result in abnormal DNA damage repair, thus contributing to the malignant progression of tumour cells. In this review, we summarise the significant roles played by XRCC in diverse tumour types. In addition, we discuss the correlation between the XRCC family members and tumour therapeutic sensitivity.
Topics: Humans; X-Rays; Neoplasms; DNA Repair; Carcinogenesis; DNA Damage
PubMed: 37679817
DOI: 10.1186/s12967-023-04447-2 -
Biomedicine & Pharmacotherapy =... Jan 2023Genetic instability can be caused by external factors and may also be associated with intracellular damage. At the same time, there is a large body of research... (Review)
Review
Genetic instability can be caused by external factors and may also be associated with intracellular damage. At the same time, there is a large body of research investigating the mechanisms by which genetic instability occurs and demonstrating the relationship between genomic stability and tumors. Nowadays, tumorigenesis development is one of the hottest research areas. It is a vital factor affecting tumor treatment. Mechanisms of genomic stability and tumorigenesis development are relatively complex. Researchers have been working on these aspects of research. To explore the research progress of genomic stability and tumorigenesis, development, and treatment, the authors searched PubMed with the keywords "genome instability" "chromosome instability" "DNA damage" "tumor spread" and "cancer treatment". This extracts the information relevant to this study. Results: This review introduces genomic stability, drivers of tumor development, tumor cell characteristics, tumor metastasis, and tumor treatment. Among them, immunotherapy is more important in tumor treatment, which can effectively inhibit tumor metastasis and kill tumor cells. Breakthroughs in tumorigenesis development studies and discoveries in tumor metastasis will provide new therapeutic techniques. New tumor treatment methods can effectively prevent tumor metastasis and improve the cure rate of tumors.
Topics: Humans; Genomic Instability; Cell Transformation, Neoplastic; DNA Damage; Neoplasms
PubMed: 36436493
DOI: 10.1016/j.biopha.2022.114036 -
Asian Pacific Journal of Cancer... Dec 2022The aim of this study was to assess the effect of radiation exposure, human 8-oxoguanine DNA N-glycosylase-1 (hOGG1) exon 7 genetic polymorphism and confounding factors...
OBJECTIVE
The aim of this study was to assess the effect of radiation exposure, human 8-oxoguanine DNA N-glycosylase-1 (hOGG1) exon 7 genetic polymorphism and confounding factors on DNA damage response.
METHODS
Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and alkaline Comet assay method were applied to determine the hOGG1 genetic polymorphisms and DNA damage response. A total of 80 participants were enrolled in this study, consisting of 40 radiation-exposed workers as a case group and 40 non-radiation workers as a control group.
RESULT
The genotypes frequencies for controls were Ser/Ser (35%), Ser/Cys (32.5%), and Cys/Cys (32.5%), with frequencies of alleles being 326Ser (0.52) and 326Cys (0.48), whereas the genotypes frequencies for radiation-exposed workers (cases group) were Ser/Ser (17.5%), Ser/Cys (57.5%), and Cys/Cys (25%), with frequencies of alleles being 326Ser (0.46) and 326Cys (0.54). The results indicated that DNA damage response were not significantly higher in the exposed workers than in controls (22.55 ± 6.02 versus 21.72 ± 7.14; P=0.58). The time of exposure has a significantly negative correlation with comet tail length value among radiation workers. In addition, it was found that the DNA damage response was strongly associated with age and time of exposure with a decrease of 0.6 percent (P-value: 0.008) and 0.58 percent (P-value: 0.009), respectively. Whereas gender, smoking habit, and equivalent dose were not correlated with DNA damage.
CONCLUSION
The single-nucleotide polymorphism of hOGG1 exon 7 (rs1052133) demonstrated no association with the extent of DNA damage in radiation-exposed workers.
Topics: Humans; Polymorphism, Single Nucleotide; Polymorphism, Restriction Fragment Length; DNA Damage; Genotype; Smoking; Genetic Predisposition to Disease; Case-Control Studies
PubMed: 36579980
DOI: 10.31557/APJCP.2022.23.12.4005