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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 -
Molecular Neurobiology Dec 2023Expansions of short tandem repeats (STRs) have been found to be present in more than 50 diseases and have a close connection with neurodegenerative diseases.... (Review)
Review
Expansions of short tandem repeats (STRs) have been found to be present in more than 50 diseases and have a close connection with neurodegenerative diseases. Transcriptional silencing and R-LOOP formation, RNA-mediated sequestration of RNA-binding proteins (RBPs), gain-of-function (GOF) proteins containing expanded repeats, and repeat-associated non-AUG (RAN) translation of toxic repeat peptides are some potential molecular mechanisms underlying STR expansion disorders. R-LOOP, a byproduct of transcription, is a three-stranded nucleic acid structure with abnormal accumulation that participates in the pathogenesis of STR expansion disorders by inducing DNA damage and genome instability. R-LOOPs can engender a series of DNA damage, such as DNA double-strand breaks (DSBs), single-strand breaks (SSBs), DNA recombination, or mutations in the DNA replication, transcription, or repair processes. In this review, we provide an in-depth discussion of recent advancements in R-LOOP and systematically elaborate on its genetic destabilizing effects in several neurodegenerative diseases. These molecular mechanisms will provide novel targets for drug design and therapeutic upgrading of these devastating diseases.
Topics: Humans; Neurodegenerative Diseases; R-Loop Structures; DNA Breaks, Double-Stranded; Microsatellite Repeats; DNA
PubMed: 37540313
DOI: 10.1007/s12035-023-03531-4 -
Life Sciences Oct 2023DNA damage caused by internal or external factors lead to increased genomic instability and various diseases. The DNA damage response (DDR) is a crucial mechanism that... (Review)
Review
DNA damage caused by internal or external factors lead to increased genomic instability and various diseases. The DNA damage response (DDR) is a crucial mechanism that maintaining genomic stability through detecting and repairing DNA damage timely. Post-translational modifications (PTMs) play significant roles in regulation of DDR. Among the present PTMs, crotonylation has emerged as a novel identified modification that is involved in a wide range of biological processes including gene expression, spermatogenesis, cell cycle, and the development of diverse diseases. In the past decade, numerous crotonylation sites have been identified in histone and non-histone proteins, leading to a more comprehensive and deep understanding of the function and mechanisms in protein crotonylation. This review provides a comprehensive overview of the regulatory mechanisms of protein crotonylation and the effect of crotonylation in DDR. Furthermore, the effect of protein crotonylation in tumor development and progression is presented, to inspire and explore the novel strategies for tumor therapy.
Topics: Male; Humans; Histones; Cell Cycle; Cell Division; DNA Damage; Genomic Instability; Biological Phenomena
PubMed: 37652154
DOI: 10.1016/j.lfs.2023.122059 -
ELife Sep 2023Checkpoint activation after DNA damage causes a transient cell cycle arrest by suppressing cyclin-dependent kinases (CDKs). However, it remains largely elusive how cell...
Checkpoint activation after DNA damage causes a transient cell cycle arrest by suppressing cyclin-dependent kinases (CDKs). However, it remains largely elusive how cell cycle recovery is initiated after DNA damage. In this study, we discovered the upregulated protein level of MASTL kinase hours after DNA damage. MASTL promotes cell cycle progression by preventing PP2A/B55-catalyzed dephosphorylation of CDK substrates. DNA damage-induced MASTL upregulation was caused by decreased protein degradation, and was unique among mitotic kinases. We identified E6AP as the E3 ubiquitin ligase that mediated MASTL degradation. MASTL degradation was inhibited upon DNA damage as a result of the dissociation of E6AP from MASTL. E6AP depletion reduced DNA damage signaling, and promoted cell cycle recovery from the DNA damage checkpoint, in a MASTL-dependent manner. Furthermore, we found that E6AP was phosphorylated at Ser-218 by ATM after DNA damage and that this phosphorylation was required for its dissociation from MASTL, the stabilization of MASTL, and the timely recovery of cell cycle progression. Together, our data revealed that ATM/ATR-dependent signaling, while activating the DNA damage checkpoint, also initiates cell cycle recovery from the arrest. Consequently, this results in a timer-like mechanism that ensures the transient nature of the DNA damage checkpoint.
Topics: Cell Cycle Checkpoints; Cell Cycle; Cell Division; Cyclin-Dependent Kinases; DNA Damage
PubMed: 37672026
DOI: 10.7554/eLife.86976 -
Journal of Microbiological Methods Dec 2023Bacterial-based genotoxicity test systems play a significant role in the detection and evaluation of genotoxicity in vitro and have gained importance due to attributes... (Review)
Review
Bacterial-based genotoxicity test systems play a significant role in the detection and evaluation of genotoxicity in vitro and have gained importance due to attributes like wide applicability, speed, high sensitivity, good reproducibility, and simplicity. The Salmonella microsomal mutagenicity assay was created by Ames and colleagues at the beginning of the 1970s, and it was based on the fundamental notion that in auxotrophic bacterial strains with inhibited growth, a mutant gene would revert to its original state on exposure to genotoxicants. This is the most successful and widely used in vitro genotoxicity test. Later, a number of additional test systems that incorporated DNA repair mechanisms including the bacterial SOS response were created. Genetic engineering has further provided significant advancement in these test systems with the development of highly sophisticated bacterial tester strains with significantly increased sensitivity to evaluate the chemical nature of hazardous substances and pollutants. These bacterial bioassays render an opportunity to detect the defined effects of compounds at the molecular level. In this review, all the aspects related to the bacterial system in genotoxicity assessment have been summarized and their role is elaborated concerning real-time requirements and future perspectives.
Topics: Reproducibility of Results; DNA Damage; Mutagenicity Tests; Bacteria; Mutagenesis
PubMed: 38008307
DOI: 10.1016/j.mimet.2023.106860 -
International Journal of Molecular... May 2024Given life's dependence on genome maintenance, unsurprisingly, investigations of the molecular processes involved in protecting the genome or, failing this, repairing...
Given life's dependence on genome maintenance, unsurprisingly, investigations of the molecular processes involved in protecting the genome or, failing this, repairing damages to and alterations introduced into genetic material are at the forefront of current research [...].
Topics: Humans; DNA Repair; Animals; Genome; Genomic Instability; DNA Damage
PubMed: 38791170
DOI: 10.3390/ijms25105131 -
DNA Repair Oct 2023Transcription-blocking lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which prevents DNA damage-induced cellular...
Transcription-blocking lesions are specifically targeted by transcription-coupled nucleotide excision repair (TC-NER), which prevents DNA damage-induced cellular toxicity and maintains proper transcriptional processes. TC-NER is initiated by the stalling of RNA polymerase II (RNAPII), which triggers the assembly of TC-NER-specific proteins, namely CSB, CSA and UVSSA, which collectively control and drive TC-NER progression. Previous research has revealed molecular functions for these proteins, however, exact mechanisms governing the initiation and regulation of TC-NER, particularly at low UV doses have remained elusive, partly due to technical constraints. In this study, we employ knock-in cell lines designed to target the endogenous CSB gene locus with mClover, a GFP variant. Through live cell imaging, we uncover the intricate molecular dynamics of CSB in response to physiologically relevant UV doses. We showed that the DNA damage-induced association of CSB with chromatin is tightly regulated by the CSA-containing ubiquitin-ligase CRL complex (CRL4). Combining the CSB-mClover knock-in cell line with SILAC-based GFP-mediated complex isolation and mass-spectrometry-based proteomics, revealed novel putative CSB interactors as well as discernible variations in complex composition during distinct stages of TC-NER progression. Our work not only provides molecular insight into TC-NER, but also illustrates the versatility of endogenously tagging fluorescent and affinity tags.
Topics: DNA Repair; DNA Damage; Cell Line; Chromatin; Mass Spectrometry
PubMed: 37716192
DOI: 10.1016/j.dnarep.2023.103566 -
Cell Systems Jul 2023Genotoxic stress in mammalian cells, including those caused by anti-cancer chemotherapy, can induce temporary cell-cycle arrest, DNA damage-induced senescence (DDIS), or...
Genotoxic stress in mammalian cells, including those caused by anti-cancer chemotherapy, can induce temporary cell-cycle arrest, DNA damage-induced senescence (DDIS), or apoptotic cell death. Despite obvious clinical importance, it is unclear how the signals emerging from DNA damage are integrated together with other cellular signaling pathways monitoring the cell's environment and/or internal state to control different cell fates. Using single-cell-based signaling measurements combined with tensor partial least square regression (t-PLSR)/principal component analysis (PCA) analysis, we show that JNK and Erk MAPK signaling regulates the initiation of cell senescence through the transcription factor AP-1 at early times after doxorubicin-induced DNA damage and the senescence-associated secretory phenotype (SASP) at late times after damage. These results identify temporally distinct roles for signaling pathways beyond the classic DNA damage response (DDR) that control the cell senescence decision and modulate the tumor microenvironment and reveal fundamental similarities between signaling pathways responsible for oncogene-induced senescence (OIS) and senescence caused by topoisomerase II inhibition. A record of this paper's transparent peer review process is included in the supplemental information.
Topics: Animals; DNA Topoisomerases, Type II; Cellular Senescence; Signal Transduction; MAP Kinase Signaling System; DNA Damage; Mammals
PubMed: 37473730
DOI: 10.1016/j.cels.2023.06.005 -
Genes Apr 2024DNA damage causes the mutations that are the principal source of genetic variation. DNA damage detection and repair mechanisms therefore play a determining role in... (Review)
Review
DNA damage causes the mutations that are the principal source of genetic variation. DNA damage detection and repair mechanisms therefore play a determining role in generating the genetic diversity on which natural selection acts. Speciation, it is commonly assumed, occurs at a rate set by the level of standing allelic diversity in a population. The process of speciation is driven by a combination of two evolutionary forces: genetic drift and ecological selection. Genetic drift takes place under the conditions of relaxed selection, and results in a balance between the rates of mutation and the rates of genetic substitution. These two processes, drift and selection, are necessarily mediated by a variety of mechanisms guaranteeing genome stability in any given species. One of the outstanding questions in evolutionary biology concerns the origin of the widely varying phylogenetic distribution of biodiversity across the Tree of Life and how the forces of drift and selection contribute to shaping that distribution. The following examines some of the molecular mechanisms underlying genome stability and the adaptive radiations that are associated with biodiversity and the widely varying species richness and evenness in the different eukaryotic lineages.
Topics: Genomic Instability; DNA Damage; Genetic Drift; Selection, Genetic; Animals; Humans; Adaptation, Physiological; Evolution, Molecular; DNA Repair; Phylogeny; Genetic Variation; Biodiversity
PubMed: 38674454
DOI: 10.3390/genes15040520 -
Scientific Reports Oct 2023To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by...
To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by formaldehyde. 40 adult Kunming male mice were randomly divided into four groups with different interventions. One week later, the contents of serum SOD, GR, MDA, DNA-protein crosslink (DPC), 8-hydroxydeoxyguanosine (8-OHDG) and DNA adduct were determined by ELISA. The results showed that there were statistically significant differences in the contents of SOD, GR and MDA among the four groups (P < 0.01). The activity of SOD and GR increased along with the increase of pachymaran dosage (SOD: r = 0.912, P < 0.01; GR: r = 0.857, P < 0.01), while the content of MDA showing a significant negative correlation (r = - 0.893, P < 0.01). There were statistically significant differences in the levels of DPC, 8-OHDG and DNA adduct among the four groups (DPC and DNA adduct: P < 0.01, 8-OHDG: P < 0.05), the concentration decreased along with the increase of pachymaran dosage (DPC: r = - 0.855, P < 0.01; 8-OHDG:r = - 0.412, P < 0.05, DNA adduct: γ = - 0.869, P < 0.01). It can be inferred that pachymaran can inhibit oxidative stress and DNA damage induced by formaldehyde with the dose-effect relationship.
Topics: Mice; Animals; Male; DNA Adducts; 8-Hydroxy-2'-Deoxyguanosine; DNA Damage; Oxidative Stress; Formaldehyde; Proteins; Superoxide Dismutase; Deoxyguanosine
PubMed: 37838763
DOI: 10.1038/s41598-023-44788-y