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Advances in Experimental Medicine and... 2022Growth arrest and DNA damage 45 (Gadd45) family genes, Gadd45A, Gadd45B, and GADD45 G are implicated as stress sensors that are rapidly induced upon...
Growth arrest and DNA damage 45 (Gadd45) family genes, Gadd45A, Gadd45B, and GADD45 G are implicated as stress sensors that are rapidly induced upon genotoxic/physiological stress. They are involved in regulation of various cellular functions such as DNA repair, senescence, and cell cycle control. Gadd45 family of genes serve as tumor suppressors in response to different stimuli and defects in Gadd45 pathway can give rise to oncogenesis. More recently, Gadd45 has been shown to promote gene activation by demethylation and this function is important for transcriptional regulation and differentiation during development. Gadd45 serves as an adaptor for DNA repair factors to promote removal of 5-methylcytosine from DNA at gene specific loci. Therefore, Gadd45 serves as a powerful link between DNA repair and epigenetic gene regulation.
Topics: Cell Cycle Checkpoints; Cell Cycle Proteins; DNA Damage; DNA Demethylation; DNA Repair
PubMed: 35505162
DOI: 10.1007/978-3-030-94804-7_4 -
Current Genetics Feb 2020DNA damage occurs abundantly during normal cellular proliferation. This necessitates that cellular DNA damage response and checkpoint pathways monitor the cellular DNA... (Review)
Review
DNA damage occurs abundantly during normal cellular proliferation. This necessitates that cellular DNA damage response and checkpoint pathways monitor the cellular DNA damage load and that DNA damage signaling is quantitative. Yet, how DNA lesions are counted and converted into a quantitative response remains poorly understood. We have recently obtained insights into this question investigating DNA damage signaling elicited by single-stranded DNA (ssDNA). Intriguingly, our findings suggest that local and global DNA damage signaling react differentially to increasing amounts of DNA damage. In this mini-review, we will discuss these findings and put them into perspective of current knowledge on the DNA damage response.
Topics: DNA Breaks, Double-Stranded; DNA Damage; Gene Expression Regulation; Genomic Instability; Humans; Protein Binding; Signal Transduction
PubMed: 31227863
DOI: 10.1007/s00294-019-01007-4 -
Trends in Cell Biology Aug 2023Genome integrity is constantly challenged by endogenous and exogenous insults that cause DNA damage. To cope with these threats, cells have a surveillance mechanism,... (Review)
Review
Genome integrity is constantly challenged by endogenous and exogenous insults that cause DNA damage. To cope with these threats, cells have a surveillance mechanism, known as the DNA damage response (DDR), to repair any lesions. Although transcription has long been implicated in DNA repair, how transcriptional reprogramming is coordinated with the DDR is just beginning to be understood. In this review, we highlight recent advances in elucidating the molecular mechanisms underlying major transcriptional events, including RNA polymerase (Pol) II stalling and transcriptional silencing and recovery, which occur in response to DNA damage. Furthermore, we discuss how such transcriptional adaptation contributes to sensing and eliminating damaged DNA and how it can jeopardize genome integrity when it goes awry.
Topics: Humans; Transcription, Genetic; DNA Damage; DNA Repair; RNA Polymerase II
PubMed: 36513571
DOI: 10.1016/j.tcb.2022.11.010 -
FEMS Microbiology Reviews Jan 2021What is the origin of mutations? In contrast to the naïve notion that mutations are unfortunate accidents, genetic research in microorganisms has demonstrated that most... (Review)
Review
What is the origin of mutations? In contrast to the naïve notion that mutations are unfortunate accidents, genetic research in microorganisms has demonstrated that most mutations are created by genetically encoded error-prone repair mechanisms. However, error-free repair pathways also exist, and it is still unclear how cells decide when to use one repair method or the other. Here, we summarize what is known about the DNA damage tolerance mechanisms (also known as post-replication repair) for perhaps the best-studied organism, the yeast Saccharomyces cerevisiae. We describe the latest research, which has established the existence of at least two error-free and two error-prone inter-related mechanisms of damage tolerance that compete for the handling of spontaneous DNA damage. We explore what is known about the induction of mutations by DNA damage. We point to potential paradoxes and to open questions that still remain unanswered.
Topics: DNA Damage; DNA Repair; Mutagenesis; Mutation; Saccharomyces cerevisiae
PubMed: 32840566
DOI: 10.1093/femsre/fuaa038 -
Molecular Cell Oct 2023In recent years, increasing evidence has highlighted the profound connection between DNA damage repair and the activation of immune responses. We spoke with researchers...
In recent years, increasing evidence has highlighted the profound connection between DNA damage repair and the activation of immune responses. We spoke with researchers about their mechanistic interplays and the implications for cancer and other diseases.
Topics: DNA Damage; DNA Repair; Signal Transduction; Immunity
PubMed: 37863025
DOI: 10.1016/j.molcel.2023.09.022 -
Chemical Research in Toxicology Feb 2023Higher stress and anxiety levels are often reported globally. While anecdotal evidence has attributed a myriad of health conditions to stress, the mechanisms are often...
Higher stress and anxiety levels are often reported globally. While anecdotal evidence has attributed a myriad of health conditions to stress, the mechanisms are often overlooked. Understanding the role of stress hormones on DNA damage/oxidative stress has implications for disease.
Topics: Oxidative Stress; DNA Damage
PubMed: 36661325
DOI: 10.1021/acs.chemrestox.2c00336 -
Journal of Assisted Reproduction and... Jul 2020
Topics: Animals; DNA Damage; DNA Repair; Female; Humans; Oocytes; Oxidative Stress
PubMed: 32671733
DOI: 10.1007/s10815-020-01889-1 -
Methods in Molecular Biology (Clifton,... 2023After DNAs are damaged, DNA repair proteins accumulate and are activated at the DNA damaged site. These accumulated proteins are visualized as foci by fluorescent...
After DNAs are damaged, DNA repair proteins accumulate and are activated at the DNA damaged site. These accumulated proteins are visualized as foci by fluorescent immunocytochemistry technique. This allows the DNA damage responses in interphase nuclei to be detected; it was earlier times difficult to analyze DNA damage in situ. In order to analyze DNA damage in interphase cells, either DNA is extracted to assay breaks biochemically, or premature chromosome condensation is conducted to observe as chromatin breaks. Although DNA damage-induced foci are typically analyzed in interphase cells, these foci can be also visualized on mitotic chromosomes. The foci where the repair proteins accumulate at the damage site is observed as mitotic chromosome break site. Since mitotic cells attach loosely or not attached to cell culture vessels, it is difficult to analyze foci on chromosomes in culture vessels under a microscope, so metaphase chromosome spread must be prepared for accurate analysis. The cytocentrifuge system is an ideal method to adhere mitotic cells to microscope slides for the fluorescent immunocytochemistry. This chapter introduces cytocentrifuge method to prepare metaphase spread for DNA damage foci analysis.
Topics: Chromosomes; DNA; DNA Damage; Interphase; Metaphase
PubMed: 36066713
DOI: 10.1007/978-1-0716-2433-3_10 -
Frontiers in Immunology 2021The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that... (Review)
Review
The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.
Topics: Cytosol; DNA Damage; Humans; Immunity, Innate; Membrane Proteins; Nucleic Acids; Receptors, Pattern Recognition; Signal Transduction
PubMed: 33981307
DOI: 10.3389/fimmu.2021.660560 -
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