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Journal of Molecular Biology Feb 2024Genomic stability relies on a multifaceted and evolutionarily conserved DNA damage response (DDR). In multicellular organisms, an integral facet of the DDR involves the... (Review)
Review
Genomic stability relies on a multifaceted and evolutionarily conserved DNA damage response (DDR). In multicellular organisms, an integral facet of the DDR involves the activation of the immune system to eliminate cells with persistent DNA damage. Recent research has shed light on a complex array of nucleic acid sensors crucial for innate immune activation in response to oncogenic stress-associated DNA damage, a process vital for suppressing tumor formation. Yet, these immune sensing pathways may also be co-opted to foster tolerance of chromosomal instability, thereby driving cancer progression. This review aims to provide an updated overview of how the innate immune system detects and responds to DNA damage. An improved understanding of the regulatory intricacies governing this immune response may uncover new avenues for cancer prevention and therapeutic intervention.
Topics: Humans; DNA Damage; DNA Repair; Neoplasms; Innate Immunity Recognition
PubMed: 38159716
DOI: 10.1016/j.jmb.2023.168424 -
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 -
Radiation Research Jun 2022The biological effects of ultrasound may be classified into thermal and nonthermal mechanisms. The nonthermal effects may be further classified into cavitational and...
The biological effects of ultrasound may be classified into thermal and nonthermal mechanisms. The nonthermal effects may be further classified into cavitational and noncavitational mechanisms. DNA damage induced by ultrasound is considered to be related to nonthermal cavitations. For this aspect, many in vitro studies on DNA have been conducted for evaluating the safety of diagnostic ultrasound, particularly in fetal imaging. Technological advancement in detecting DNA damage both in vitro and in vivo have elucidated the mechanism of DNA damage formation and their cellular response. Damage to DNA, and the residual damages after DNA repair are implicated in the biological effects. Here, we discuss the historical evidence of ultrasound on DNA damage and the mechanism of DNA damage formation both in vitro and in vivo, compared with those induced by ionizing radiation. We also offer a commentary on the safety of ultrasound over X-ray-based imaging. Also, understanding the various mechanisms involved in the bioeffects of ultrasound will lead us to alternative strategies for use of ultrasound for therapy.
Topics: DNA Damage; DNA Repair; Radiation, Ionizing; Ultrasonography
PubMed: 35275998
DOI: 10.1667/RADE-21-00140.1.S1 -
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 -
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 Jan 2024The genetic information stored in DNA is under continuous threat by endogenous and environmental sources of DNA damage. Cells have evolved multiple DNA repair pathways...
The genetic information stored in DNA is under continuous threat by endogenous and environmental sources of DNA damage. Cells have evolved multiple DNA repair pathways that function in overlapping manners, with principles shared across species. Here, we depict the main DNA repair pathways cells rely on, with the primary lesions they are tackling, along with key players and main DNA transactions. To view this SnapShot, open or download the PDF.
Topics: DNA Damage; DNA; DNA Repair
PubMed: 38181759
DOI: 10.1016/j.molcel.2023.11.030 -
Archives of Toxicology Jun 2021Pyrrolizidine alkaloids (PAs) and PA N-oxides are common phytotoxins produced by over 6000 plant species. Humans are frequently exposed to PAs via ingestion of... (Review)
Review
Pyrrolizidine alkaloids (PAs) and PA N-oxides are common phytotoxins produced by over 6000 plant species. Humans are frequently exposed to PAs via ingestion of PA-containing herbal products or PA-contaminated foods. PAs require metabolic activation to form pyrrole-protein adducts and pyrrole-DNA adducts which lead to cytotoxicity and genotoxicity. Individual PAs differ in their metabolic activation patterns, which may cause significant difference in toxic potency of different PAs. This review discusses the current knowledge and recent advances of metabolic pathways of different PAs, especially the metabolic activation and metabolism-mediated cytotoxicity and genotoxicity, and the risk evaluation methods of PA exposure. In addition, this review provides perspectives of precision toxicity assessment strategies and biomarker development for the risk control and translational investigations of human intoxication by PAs.
Topics: Animals; Biomarkers; DNA Adducts; DNA Damage; Humans; Mutagens; Pyrrolizidine Alkaloids; Risk Assessment
PubMed: 34003343
DOI: 10.1007/s00204-021-03060-w -
ELife Jun 2023Repair of DNA double strand breaks (DSBs) is integral to preserving genomic integrity. Therefore, defining the mechanisms underlying DSB repair will enhance our...
Repair of DNA double strand breaks (DSBs) is integral to preserving genomic integrity. Therefore, defining the mechanisms underlying DSB repair will enhance our understanding of how defects in these pathways contribute to human disease and could lead to the discovery of new approaches for therapeutic intervention. Here, we established a panel of HaloTagged DNA damage response factors in U2OS cells which enables concentration-dependent protein labeling by fluorescent HaloTag ligands. Genomic insertion of HaloTag at the endogenous loci of these repair factors preserves expression levels and proteins retain proper subcellular localization, foci-forming ability, and functionally support DSB repair. We systematically analyzed total cellular protein abundance, measured recruitment kinetics to laser-induced DNA damage sites, and defined the diffusion dynamics and chromatin binding characteristics by live-cell single-molecule imaging. Our work demonstrates that the Shieldin complex, a critical factor in end-joining, does not exist in a preassembled state and that relative accumulation of these factors at DSBs occurs with different kinetics. Additionally, live-cell single-molecule imaging revealed the constitutive interaction between MDC1 and chromatin mediated by its PST repeat domain. Altogether, our studies demonstrate the utility of single-molecule imaging to provide mechanistic insights into DNA repair, which will serve as a powerful resource for characterizing the biophysical properties of DNA repair factors in living cells.
Topics: Humans; Tumor Suppressor p53-Binding Protein 1; DNA Repair; Chromatin; DNA Breaks, Double-Stranded; DNA Damage
PubMed: 37341699
DOI: 10.7554/eLife.87086 -
Trends in Genetics : TIG Nov 2021DNA damage-inducible miRNAs are likely to be functional in the DNA damage response. This response can elicit damage resolution and cell survival or apoptosis. The...
DNA damage-inducible miRNAs are likely to be functional in the DNA damage response. This response can elicit damage resolution and cell survival or apoptosis. The current, albeit incomplete, picture suggests that miRNAs can affect cell fate via modulation of key response proteins, but the question is, who's in charge?
Topics: Apoptosis; Cell Differentiation; DNA Damage; DNA Repair; MicroRNAs
PubMed: 34281698
DOI: 10.1016/j.tig.2021.06.018 -
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