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The International Journal of... Sep 2023Cisplatin, a widely prescribed chemotherapeutic agent for treating solid tumors, induces DNA adducts and activates cellular defense mechanisms, including DNA repair,...
Cisplatin, a widely prescribed chemotherapeutic agent for treating solid tumors, induces DNA adducts and activates cellular defense mechanisms, including DNA repair, cell cycle checkpoint control, and apoptosis. Considering the circadian rhythmicity displayed by most chemotherapeutic agents and their varying therapeutic efficacy based on treatment timing, our study aimed to investigate whether the circadian clock system influences the DNA damage responses triggered by cisplatin in synchronized cells. We examined the DNA damage responses in circadian-synchronized wild-type mouse embryonic fibroblasts (WT-MEF; clock-proficient cells), cryptochrome1 and 2 double knock-out MEF (CRY; clock-deficient cells), and mouse hepatocarcinoma Hepa1c1c7 cells. Varying the treatment time resulted in a significant difference in the rate of platinum-DNA adduct removal specifically in circadian-synchronized WT-MEF, while CRY did not exhibit such variation. Moreover, diurnal variation in other DNA damage responses, such as cell cycle checkpoint activity indicated by p53 phosphorylation status and apoptosis measured by DNA break frequency, was observed only in circadian-synchronized WT-MEF, not in CRY or mouse hepatocarcinoma Hepa1c1c7 cells. These findings highlight that the DNA damage responses triggered by cisplatin are indeed governed by circadian control exclusively in clock-proficient cells. This outcome bears potential implications for enhancing or devising chronotherapy approaches for cancer patients.
Topics: Animals; Mice; Cisplatin; DNA Adducts; DNA Damage; Fibroblasts; DNA Repair; Circadian Clocks; Neoplasms; Apoptosis
PubMed: 37574041
DOI: 10.1016/j.biocel.2023.106454 -
Trends in Genetics : TIG Dec 2023Genome integrity and maintenance are essential for the viability of all organisms. A wide variety of DNA damage types have been described, but double-strand breaks... (Review)
Review
Genome integrity and maintenance are essential for the viability of all organisms. A wide variety of DNA damage types have been described, but double-strand breaks (DSBs) stand out as one of the most toxic DNA lesions. Two major pathways account for the repair of DSBs: homologous recombination (HR) and non-homologous end joining (NHEJ). Both pathways involve complex DNA transactions catalyzed by proteins that sequentially or cooperatively work to repair the damage. Single-molecule methods allow visualization of these complex transactions and characterization of the protein:DNA intermediates of DNA repair, ultimately allowing a comprehensive breakdown of the mechanisms underlying each pathway. We review current understanding of the HR and NHEJ responses to DSBs in eukaryotic cells, with a particular emphasis on recent advances through the use of single-molecule techniques.
Topics: DNA Breaks, Double-Stranded; DNA Repair; DNA; DNA Damage; DNA End-Joining Repair
PubMed: 37806853
DOI: 10.1016/j.tig.2023.09.004 -
International Journal of Molecular... Dec 2023DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O-alkylguanine and O-alkylthymine bases... (Review)
Review
DNA alkyltransferase and alkyltransferase-like family proteins are responsible for the repair of highly mutagenic and cytotoxic O-alkylguanine and O-alkylthymine bases in DNA. Their mechanism involves binding to the damaged DNA and flipping the base out of the DNA helix into the active site pocket in the protein. Alkyltransferases then directly and irreversibly transfer the alkyl group from the base to the active site cysteine residue. In contrast, alkyltransferase-like proteins recruit nucleotide excision repair components for O-alkylguanine elimination. One or more of these proteins are found in all kingdoms of life, and where this has been determined, their overall DNA repair mechanism is strictly conserved between organisms. Nevertheless, between species, subtle as well as more extensive differences that affect target lesion preferences and/or introduce additional protein functions have evolved. Examining these differences and their functional consequences is intricately entwined with understanding the details of their DNA repair mechanism(s) and their biological roles. In this review, we will present and discuss various aspects of the current status of knowledge on this intriguing protein family.
Topics: Alkyl and Aryl Transferases; Cysteine; DNA Repair; DNA
PubMed: 38203633
DOI: 10.3390/ijms25010463 -
Tumour Virus Research Dec 2023Approximately 20 % of human cancers are associated with virus infection. DNA tumor viruses can induce tumor formation in host cells by disrupting the cell's DNA... (Review)
Review
Approximately 20 % of human cancers are associated with virus infection. DNA tumor viruses can induce tumor formation in host cells by disrupting the cell's DNA replication and repair mechanisms. Specifically, these viruses interfere with the host cell's DNA damage response (DDR), which is a complex network of signaling pathways that is essential for maintaining the integrity of the genome. DNA tumor viruses can disrupt these pathways by expressing oncoproteins that mimic or inhibit various DDR components, thereby promoting genomic instability and tumorigenesis. Recent studies have highlighted the molecular mechanisms by which DNA tumor viruses interact with DDR components, as well as the ways in which these interactions contribute to viral replication and tumorigenesis. Understanding the interplay between DNA tumor viruses and the DDR pathway is critical for developing effective strategies to prevent and treat virally associated cancers. In this review, we discuss the current state of knowledge regarding the mechanisms by which human papillomavirus (HPV), merkel cell polyomavirus (MCPyV), Kaposi's sarcoma-associated herpesvirus (KSHV), and Epstein-Barr virus (EBV) interfere with DDR pathways to facilitate their respective life cycles, and the consequences of such interference on genomic stability and cancer development.
Topics: Humans; Epstein-Barr Virus Infections; Herpesvirus 4, Human; DNA Tumor Viruses; Neoplasms; Herpesvirus 8, Human; DNA Repair; Carcinogenesis
PubMed: 37918513
DOI: 10.1016/j.tvr.2023.200272 -
Science (New York, N.Y.) Sep 2023Pioneer of cell mutagenesis and DNA repair research.
Pioneer of cell mutagenesis and DNA repair research.
Topics: DNA Repair; Genetics; Mutagenesis; United States
PubMed: 37676948
DOI: 10.1126/science.adk1028 -
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 Aug 2023Errol Clive Friedberg, who died at the end of March 2023, was the first Editor-in-Chief of the journal DNA Repair. He was an influential DNA repair scientist, a...
Errol Clive Friedberg, who died at the end of March 2023, was the first Editor-in-Chief of the journal DNA Repair. He was an influential DNA repair scientist, a synthesizer of ideas, and an accomplished historian. In addition to the research accomplishments of his laboratory groups, Errol Friedberg provided enormous service to the DNA repair community though organizing major conferences, journal editing, and writing. His many books include texts about DNA repair, histories of the field, and biographies of several pioneers of molecular biology.
Topics: History, 20th Century; DNA Repair; Molecular Biology; Writing
PubMed: 37301015
DOI: 10.1016/j.dnarep.2023.103516 -
Structure (London, England : 1993) Aug 2023The ability of humans to maintain the integrity of the genome is imperative for cellular survival. DNA double-strand breaks (DSBs) are considered the most critical type...
The ability of humans to maintain the integrity of the genome is imperative for cellular survival. DNA double-strand breaks (DSBs) are considered the most critical type of DNA lesion, which can ultimately lead to diseases including cancer. Non-homologous end joining (NHEJ) is one of two core mechanisms utilized to repair DSBs. DNA-PK is a key component in this process and has recently been shown to form alternate long-range synaptic dimers. This has led to the proposal that these complexes can be formed before transitioning to a short-range synaptic complex. Here we present cryo-EM data representing an NHEJ supercomplex consisting of a trimer of DNA-PK in complex with XLF, XRCC4, and DNA Ligase IV. This trimer represents a complex of both long-range synaptic dimers. We discuss the potential role of the trimeric structure, and possible higher order oligomers, as structural intermediates in the NHEJ mechanism, or as functional DNA repair centers.
Topics: Humans; DNA Repair Enzymes; Cryoelectron Microscopy; DNA Repair; DNA End-Joining Repair; DNA Ligase ATP; DNA-Activated Protein Kinase; DNA
PubMed: 37311458
DOI: 10.1016/j.str.2023.05.013 -
Aging Cell Feb 2024Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether...
Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging.
Topics: Humans; Mice; Animals; Aging, Premature; Aging; DNA Repair; DNA Methylation; Proteins; Epigenesis, Genetic; DNA
PubMed: 38140713
DOI: 10.1111/acel.14058 -
Frontiers in Immunology 2023As one of the most common malignancies worldwide, breast cancer (BC) exhibits high heterogeneity of molecular phenotypes. The evolving view regarding DNA damage repair...
BACKGROUND
As one of the most common malignancies worldwide, breast cancer (BC) exhibits high heterogeneity of molecular phenotypes. The evolving view regarding DNA damage repair (DDR) is that it is context-specific and heterogeneous, but its role in BC remains unclear.
METHODS
Multi-dimensional data of transcriptomics, genomics, and single-cell transcriptome profiling were obtained to characterize the DDR-related features of BC. We collected 276 DDR-related genes based on the Molecular Signature Database (MSigDB) database and previous studies. We acquired public datasets included the SCAN-B dataset (GEO: GSE96058), METABRIC database, and TCGA-BRCA database. Corresponding repositories such as transcriptomics, genomics, and clinical information were also downloaded. We selected scRNA-seq data from GEO: GSE176078, GSE114727, GSE161529, and GSE158724. Bulk RNA-seq data from GEO: GSE176078, GSE18728, GSE5462, GSE20181, and GSE130788 were extracted for independent analyses.
RESULTS
The DDR classification was constructed in the SCAN-B dataset (GEO: GSE96058) and METABRIC database, Among BC patients, there were two clusters with distinct clinical and molecular characteristics: the DDR-suppressed cluster and the DDR-active cluster. A superior survival rate is found for tumors in the DDR-suppressed cluster, while those with the DDR-activated cluster tend to have inferior prognoses and clinically aggressive behavior. The DDR classification was validated in the TCGA-BRCA cohort and shown similar results. We also found that two clusters have different pathway activities at the genomic level. Based on the intersection of the different expressed genes among these cohorts, we found that PRAME might play a vital role in DDR. The DDR classification was then enabled by establishing a DDR score, which was verified through multilayer cohort analysis. Furthermore, our results revealed that malignant cells contributed more to the DDR score at the single-cell level than nonmalignant cells. Particularly, immune cells with immunosuppressive properties (such as FOXP3+ CD4+ T cells) displayed higher DDR scores among those with distinguishable characteristics.
CONCLUSION
Collectively, this study performs general analyses of DDR heterogeneity in BC and provides insight into the understanding of individualized molecular and clinicopathological mechanisms underlying unique DDR profiles.
Topics: Humans; Female; Breast Neoplasms; Multiomics; CD4-Positive T-Lymphocytes; DNA Repair; DNA Damage; Antigens, Neoplasm
PubMed: 38022619
DOI: 10.3389/fimmu.2023.1297180