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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 -
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 -
Cell Death & Disease Jul 2023DNA repair is a tightly coordinated stress response to DNA damage, which is critical for preserving genome integrity. Accruing evidence suggests that metabolic pathways...
DNA repair is a tightly coordinated stress response to DNA damage, which is critical for preserving genome integrity. Accruing evidence suggests that metabolic pathways have been correlated with cellular response to DNA damage. Here, we show that fatty acid oxidation (FAO) is a crucial regulator of DNA double-strand break repair, particularly homologous recombination repair. Mechanistically, FAO contributes to DNA repair by activating poly(ADP-ribose) polymerase 1 (PARP1), an enzyme that detects DNA breaks and promotes DNA repair pathway. Upon DNA damage, FAO facilitates PARP1 acetylation by providing acetyl-CoA, which is required for proper PARP1 activity. Indeed, cells reconstituted with PARP1 acetylation mutants display impaired DNA repair and enhanced sensitivity to DNA damage. Consequently, FAO inhibition reduces PARP1 activity, leading to increased genomic instability and decreased cell viability upon DNA damage. Finally, our data indicate that FAO serves as an important participant of cellular response to DNA damage, supporting DNA repair and genome stability.
Topics: Humans; Acetylation; DNA Repair; DNA; Poly (ADP-Ribose) Polymerase-1; DNA Breaks, Double-Stranded; DNA Damage; Fatty Acids
PubMed: 37454129
DOI: 10.1038/s41419-023-05968-w -
Cells Feb 2022DNA damage in cells can occur physiologically or may be induced by exogenous factors. Genotoxic damage may cause cancer, ageing, serious developmental diseases and... (Review)
Review
DNA damage in cells can occur physiologically or may be induced by exogenous factors. Genotoxic damage may cause cancer, ageing, serious developmental diseases and anomalies. If the damage occurs in the germline, it can potentially lead to infertility or chromosomal and genetic aberrations in the developing embryo. Mammalian oocytes, the female germ cells, are produced before birth, remaining arrested at the prophase stage of meiosis over a long period of time. During this extensive state of arrest the oocyte may be exposed to different DNA-damaging insults for months, years or even decades. Therefore, it is of great importance to understand how these cells respond to DNA damage. In this review, we summarize the most recent developments in the understanding of the DNA damage response mechanisms that function in fully grown mammalian oocytes.
Topics: Animals; DNA Damage; Female; Infertility; Mammals; Meiosis; Oocytes
PubMed: 35269420
DOI: 10.3390/cells11050798 -
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 -
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 -
International Journal of Molecular... Jun 2021Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging... (Review)
Review
Many human cancers exhibit defects in key DNA damage response elements that can render tumors insensitive to the cell death-promoting properties of DNA-damaging therapies. Using agents that directly induce apoptosis by targeting apoptotic components, rather than relying on DNA damage to indirectly stimulate apoptosis of cancer cells, may overcome classical blocks exploited by cancer cells to evade apoptotic cell death. However, there is increasing evidence that cells surviving sublethal exposure to classical apoptotic signaling may recover with newly acquired genomic changes which may have oncogenic potential, and so could theoretically spur the development of subsequent cancers in cured patients. Encouragingly, cells surviving sublethal necroptotic signaling did not acquire mutations, suggesting that necroptosis-inducing anti-cancer drugs may be less likely to trigger therapy-related cancers. We are yet to develop effective direct inducers of other cell death pathways, and as such, data regarding the consequences of cells surviving sublethal stimulation of those pathways are still emerging. This review details the currently known mutagenic consequences of cells surviving different cell death signaling pathways, with implications for potential oncogenic transformation. Understanding the mechanisms of mutagenesis associated (or not) with various cell death pathways will guide us in the development of future therapeutics to minimize therapy-related side effects associated with DNA damage.
Topics: Animals; Cell Death; DNA Damage; Humans; Mutagenesis; Mutation; Neoplasms
PubMed: 34200309
DOI: 10.3390/ijms22116144 -
International Journal of Molecular... Nov 2020Ionizing radiation is widely used in medicine, both as a diagnostic tool and as a therapeutic agent [...].
Ionizing radiation is widely used in medicine, both as a diagnostic tool and as a therapeutic agent [...].
Topics: DNA Breaks, Double-Stranded; DNA Breaks, Single-Stranded; DNA Damage; Humans; Neoplasms; Radiation, Ionizing
PubMed: 33139616
DOI: 10.3390/ijms21218188 -
Molecular Cell Apr 2023In this issue, Cieśla et al. report a translation regulation through ALKBH5-mediated 5'-UTR mA demethylation of the SF3B1 transcript during leukemic transformation....
In this issue, Cieśla et al. report a translation regulation through ALKBH5-mediated 5'-UTR mA demethylation of the SF3B1 transcript during leukemic transformation. The SF3B1 protein maintains efficient splicing and expression of transcripts encoding DNA damage repair components to restrain excessive DNA damage.
Topics: RNA Splicing Factors; Mutation; Phosphoproteins; RNA Splicing; DNA Damage
PubMed: 37028412
DOI: 10.1016/j.molcel.2023.02.019 -
Molecules (Basel, Switzerland) Aug 2019DNA polymerase (pol) kappa is a Y-family translesion DNA polymerase conserved throughout all domains of life. Pol kappa is special6 ized for the ability to copy DNA... (Review)
Review
DNA polymerase (pol) kappa is a Y-family translesion DNA polymerase conserved throughout all domains of life. Pol kappa is special6 ized for the ability to copy DNA containing minor groove DNA adducts, especially -dG adducts, as well as to extend primer termini containing DNA damage or mismatched base pairs. Pol kappa generally cannot copy DNA containing major groove modifications or UV-induced photoproducts. Pol kappa can also copy structured or non-B-form DNA, such as microsatellite DNA, common fragile sites, and DNA containing G quadruplexes. Thus, pol kappa has roles both in maintaining and compromising genomic integrity. The expression of pol kappa is altered in several different cancer types, which can lead to genome instability. In addition, many cancer-associated single-nucleotide polymorphisms have been reported in the gene, some of which are associated with poor survival and altered chemotherapy response. Because of this, identifying inhibitors of pol kappa is an active area of research. This review will address these activities of pol kappa, with a focus on lesion bypass and cellular mutagenesis.
Topics: DNA Adducts; DNA Damage; DNA Replication; DNA-Directed DNA Polymerase; G-Quadruplexes; Humans; Mutagenesis
PubMed: 31374881
DOI: 10.3390/molecules24152805