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Results for “DNA-damage repair”

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At least 19 recordsLinked to original sources
PubMed2026

Rationale and Study Design of the GUIDANCE trial: A Multicenter Phase II Trial of Maintenance Durvalumab and Olaparib After Standard Fist Line Treatment (Carboplatin/Cisplatin, Etoposide, and Durvalumab) in HRD Positive Extensive Disease (ED) Small-cell Lung Cancer (SCLC) (AIO-TRK-0124/ass).

BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis and limited therapeutic progress over recent decades. Although PD-L1 inhibitors have modestly improved survival, responses are not durable. There are no predictive biomarkers that would allow for a personalized treatment strategy. Targeting DNA damage repair deficiencies represents a promising treatment strategy in various solid tumors. Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib have demonstrated efficacy in homologous recombination deficiency (HRD)-positive tumors, and preclinical data suggest synergistic activity with immune checkpoint blockade. METHODS: GUIDANCE is a biomarker-driven, multicenter, single-arm, open-label phase II trial evaluating maintenance therapy with durvalumab and olaparib in patients with advanced or metastatic SCLC without progression after first-line therapy with platinum, etoposide and durvalumab. Patients are prospectively selected for HRD based on homologous recombination repair gene alterations and/or a genomic instability score. Following central prescreening, 29 patients will be enrolled. Patients receive durvalumab (1500 mg every 4 weeks) and olaparib (300 mg twice daily) until progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) by RECIST 1.1. Secondary endpoints are overall survival, safety and tolerability. Exploratory analyses include circulating tumor DNA (ctDNA) monitoring of individual TP53 mutations, assessment of SLFN11 expression, and characterization of immune cell composition via multiplex immunohistochemistry. DISCUSSION: This trial investigates a chemotherapy-free, genomically stratified maintenance strategy targeting both DNA damage repair deficiency and immune evasion in SCLC. By integrating HRD-based patient selection with concurrent PARP and immune checkpoint inhibition, GUIDANCE aims to establish a more individualized therapeutic approach and to generate a signal for further evaluation in biomarker-defined patient populations. Trial registration number EuraCT 2024-512373-27-00.

DNA-damage repair↗
PubMed1979

DNA-damaging and mutagenic effects of 1,2-dimethylhydrazine on Bacillus subtilis repair-deficient mutants.

Mutagenic, DNA-damaging, and in vivo alteration of DNA have been demonstrated for 1,2-dimethylhydrazine (DMH), a potent inducer of adenocarcinomas of the large intestine and colon of rats. These activities are pH-dependent, with 6.5 giving optimum response. There was no requirement for metabolic activation with rat-liver S9 mix when the appropriate Bacillus subtilis mutant strains were used. The Rec- strains recA8 and mc-1 were greater than 300-fold more sensitive to the DNA-damaging activity of DMH than was their isogenic wild-type parent. The DNA isolated from DMH-treated mc-1 had altered spectroscopic characteristics, and gave a greatly reduced transformation efficiency. Treatment of B. subtilis strain TKJ6321 with DMH at pH 6.5 induced His+, Met+ mutations in substantial numbers at low concentrations of this chemical. The use of B. subtilis mutants in these studies has therefore made it possible to demonstrate mutagenic and DNA-damaging activity in bacteria for this potent carcinogenic chemical.

Bacillus subtilis↗
PubMed1977

[Effect of violamycin BI on the process of excision repair in Escherichia coli K 12 following UV irradiation].

The influence of violamycin B I on the process of excision repair of DNA-damages after UV-irradiation has been studied by observing the capacity to rejoin single-strand breaks introduced in the DNA at the beginning of the repair process. The number of single-strand breaks remaining unrepaired in the DNA was higher in presence of violamycin B I. Sedimentation analysis of the DNA of unirradiated cells showed in presence of violamycin B I only a small change in the molecular weight. As a possible reason for the lower capacity of the cells to accomplish repair steps following incision in presence of violamycin B I an inhibition of the function of repair enzymes by interaction of the antibiotic with the DNA-template is discussed.

Aminoglycosides↗
PubMed2026

The KEAP1-NFE2L2/NRF2 Axis in Non-Small Cell Lung Cancer Radioresistance: Redox Homeostasis and Emerging DNA Damage Response Mechanisms.

Radioresistance and local recurrence remain major barriers to effective radiotherapy in non-small cell lung cancer (NSCLC). Loss-of-function KEAP1 alterations or activating NFE2L2 alterations can stabilize NRF2, but do not alone establish sustained transcriptional activity or functional dependency. This focused narrative review evaluates clinical radiotherapy studies and mechanistically informative preclinical studies linking the KEAP1-NFE2L2/NRF2 axis to NSCLC radioresistance. We prioritized clinical studies reporting radiotherapy-specific outcomes and preclinical studies coupling NRF2-related molecular status or perturbation with radiation-response endpoints; contextual studies informed metabolic, DNA damage response (DDR), immune and normal-lung effects. Evidence most consistently supports NRF2-mediated redox protection through glutathione-dependent defense, cellular reducing capacity and antioxidant enzymes, limiting radiation-induced reactive oxygen species (ROS) accumulation and oxidative injury. Limited studies further suggest that NRF2 may affect DNA-damage signaling, checkpoint control and repair. The detailed RPA32-TOPBP1-ATR-CHK1 model is therefore considered proposed rather than established in NRF2-active NSCLC. Retrospective clinical studies associate pathogenic KEAP1/NFE2L2 alterations with impaired local control in some radiotherapy-treated cohorts, but do not justify treating genomic status, protein abundance, transcriptional activity and functional dependency as equivalent measures or demonstrate treatment-predictive value. NRF2-mediated normal-lung protection also constrains systemic inhibition. Prospective studies integrating molecular classification, radiation-response endpoints, local control and normal-tissue toxicity are required before biomarker-guided radiosensitization can be considered.

DNA damage response↗
PubMed2025

Arginine methylation-dependent METTL14-SMN interaction regulates RNA m6A homeostasis.

N6-methyladenosine (m6A) homeostasis is essential for development, and its dysregulation is linked to cancers and neurological disorders. However, the mechanisms regulating m6A remain unclear. Here, we identify the survival of motoneuron (SMN) protein as a novel interaction partner of METTL14, a key component of the m6A methyltransferase complex. SMN binds METTL14 via its Tudor domain in an arginine methylation-dependent manner. Mutations in the SMN Tudor domain identified in spinal muscular atrophy (SMA) disrupt its interaction with METTL14 and reduce m6A levels in patient-derived fibroblasts, linking m6A dysregulation to SMA pathology. Both SMN knockdown and SMA mutations impair m6A deposition on the mRNAs of DNA repair genes, mirroring the effects of METTL14 hypomethylation. Consequently, SMA patient fibroblasts are hypersensitive to DNA-damaging agents due to reduced levels of DNA repair gene expression. To explore the function of METTL14 arginine methylation in vivo, we generated a Mettl14 methylation-deficient mouse model (Mettl14RK). Although this model does not show SMA-like phenotypes, the mutants are partially embryonic lethal and show abnormal hematopoiesis, underscoring a role for methylated METTL14 in early development.

Methyltransferases↗
PubMed1979

Mutagenic and DNA-damaging effects of N-alkyl-N-(alpha-acetoxyalkyl)nitrosamines, models for metabolically activated N,N-dialkylnitrosamines.

Mutagenic and DNA-damaging effects of a series of N,N-dialkylnitrosamines monosubstituted at the alpha-carbon with an acetoxyl group were tested in Salmonella typhimurium, Escherichia coli, and Bacilus subtilis in the absence of metabolic activation system. The compounds comprised 8 N-alkyl-N-(acetoxymethyl)nitrosamines (alkyl=methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl) and N-butyl-N-(1-acetoxybutyl)nitrosamine. All the compounds, except one with a tert-butyl group, gave positive results in these mutagenicity and repair tests. Presumed release of alkyl cations from the corresponding alpha-acetoxy derivatives by hydrolysis and heterolysis caused mutagenic and DNA-damaging effects in the bacteria. Structure-activity correlation of the compounds was noted in these tests and discussed in regard to the mutagenicity with metabolic activation and carcinogenicity of N,N-dialkylnitrosamines. The results support the hypothesis that alpha-carbon hydroxylation is one probable mechanism involved in the metabolic activation of N,N-dialkylnitrosamines.

Bacillus subtilis↗
PubMed2026

A germline KDM3C polymorphism impairs DNA repair and sensitizes to chemoradiotherapy.

Chemoradiotherapy (CRT) is the standard-of-care therapy for many solid malignancies, yet predictive biomarkers of treatment response remain limited. We identified a germline single nucleotide polymorphism (SNP) in an intrinsically disordered region of the lysine demethylase KDM3C/JMJD1C (p.S464T) that is associated with CRT outcomes in locally advanced rectal cancers (LARC) and head and neck squamous cell carcinoma (LA-HNSCC). In silico modeling with AlphaFold predicted S464T substitution influenced interaction between phosphorylated KDM3C and RNF8 FHA domain. In cellular models, conversion of S464 to T464 increased sensitivity to DNA-damaging agents. S464T substitution impaired damage-induced MDC1-RAP80 signaling and downstream RAP80-BRCA1 colocalization. SNP carrying cells impaired DNA repair causing genotoxic stress that is associated with increased cGAS-cGAMP innate immune signaling and increased apoptosis. Population analyses with the SNP highlighted an increase incidence of UV-induced skin and other cancers, linking inherited variation in the chromatin regulatory gene KDM3C to genome instability, cancer risk, and therapeutic vulnerability.

Journal Article↗
PubMed1979

Association of poly(adenosine diphosphoribose) synthesis with DNA damage and repair in normal human lymphocytes.

A permeable cell technique was used to measure the alterations in synthesis of DNA and poly-(adenosine diphosphoribose) in normal human lymphocytes after treatment of the cells with different types of DNA-damaging agents. The lymphocytes showed an abrupt increase in the unscheduled synthesis of DNA and poly(adenosine diphosphoribose) in response to ultraviolet (UV) irradiation. The increases were apparent within 1 h and reached a maximum between 2 and 4 h after irradiation. The magnitude of the increases in DNA and poly(adenosine diphosphoribose) synthesis was dependent upon the UV dose. Alkaline CsCl gradient studies, with bromodeoxyuridine triphosphate density labeling of DNA, demonstrated that the unscheduled DNA synthesis, which occurred in response to UV irradiation, was actually a result of the repair mode of DNA synthesis. Similar increases in DNA synthesis, and poly(adenosine diphosphoribose) synthesis occurred when lymphocytes were treated with several other DNA-damaging agents, including bleomycin, N-methyl-N'-nitro-N-nitrosoguanidine or N-acetoxyacetyl aminofluorene. Treatment of lymphocytes with DNase, under conditions which allowed degradation of cellular DNA, also resulted in increased synthesis of poly(adenosine diphosphoribose). Cycloheximide did not inhibit the increase in synthesis of DNA or poly(adenosine diphosphoribose) that occurred in response to treatment with the DNA-damaging agents.

Cycloheximide↗
PubMed1978

Interindividual variation in the responses of cultured human lymphocytes to exposure from DNA damaging chemical agents: interindividual variation to carcinogen exposure.

Human population variability to standardized doses of N-acetoxy-2-acetylaminofluorene (NA-AAF) and 7, 12-dimethylbenz(a) anthracene (DMBA) was determined in cultured lymphocytes by measuring (a) differential stimulation of unscheduled DNA synthesis after 1 h induction of DNA damage by 10 micrometer NA-AAF, (b) the level of NA-AAF induced chromosome aberrations remaining after 8 h of DNA-repair synthesis, and (c) the level of [3H]DMBA bound to DNA after 18 h incubation of resting lymphocytes in 5 micrometer DMBA. All 3 parameters indicated individual variation to carcinogen exposure and were correlated to the population differences in age, sex, blood pressure and mortality rates. Males always had a greater potential to accumulate DNA-damage than did females regardless of the sampled population. DNA-damage potentials increased with increasing age, blood pressure or mortality rates. There was always proportionally greater DNA-damage potentials in the males than in females. The in vitro response of mature granulocytes to a 10 micrometer NA-AAF dose, as estimated by [3H] thymidine incorporation from unscheduled DNA synthesis, was much lower than lymphocyte response. Nevertheless, individual variations in granulocyte NA-AAF induced unscheduled DNA synthesis paralleled the inter-individual fluctuations observed in the lymphocyte responses to NA-AAF.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2017

Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy.

To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents. The difficulty in capitalizing on synthetically lethal interactions in cancer cells is that many potential targets do not possess well-defined small-molecule binding determinates. In this review, we discuss several successful campaigns to identify and leverage small-molecule inhibitors of the DNA repair proteins, from PARP1, a paradigm case for clinically successful small-molecule inhibitors, to coveted new targets, such as RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.

DNA Helicases↗
PubMed2026

Prognostic and predictive value of HRD in early triple negative breast cancer (TNBC).

This review explores the emerging role of homologous recombination deficiency (HRD) as both a prognostic and predictive biomarker in early-stage triple-negative breast cancer (TNBC). HRD arises from the defective repair of DNA double-strand breaks through homologous recombination, resulting in genomic instability and increased sensitivity to DNA-damaging agents such as platinum compounds. The review outlines the biological basis of HRD, including genomic signatures such as loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, and highlights its prevalence in TNBC compared with other breast cancer subtypes. Clinical trials have shown that HRD-positive patients often achieve higher pathological complete response rates and improved disease-free survival when treated with chemotherapy. However, conflicting evidence across trials underscores the need for more reliable and standardized methods for HRD assessment. The review also explores the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in TNBC, particularly in BRCA-mutated or HRD-positive tumors. Agents such as olaparib, talazoparib, and niraparib have demonstrated promising efficacy in both neoadjuvant and adjuvant settings with some trials suggesting that selected patients may avoid chemotherapy. Furthermore, HRD-positive tumors are characterized by increased genomic instability and a higher neoantigen burden, promoting immune cell infiltration, particularly of tumor-infiltrating lymphocytes, which may enhance responsiveness to immune checkpoint inhibitors. Overall, current evidence supports the role of HRD as a promising biomarker in TNBC. However, further research is required to refine its clinical utility and to integrate HRD testing into personalized treatment strategies, especially in combination with emerging therapies such as immunotherapy.

Humans↗
PubMed2026

Protein persulfidation emerges as a conserved component of the redox response to DNA damage.

Genotoxic stress is frequently accompanied by alterations in cellular redox homeostasis; however, the mechanisms linking redox regulation to the DNA damage response (DDR) remain incompletely understood. Here, we investigated the early redox response to DNA damage induced by methyl methanesulfonate (MMS) in Saccharomyces cerevisiae, focusing on cysteine oxidative post-translational modifications (PTM). We show that activation of the DNA damage response is accompanied by rapid redox changes that occur in the absence of a generalized oxidative stress response. MMS exposure promotes selective remodeling of cysteine oxidative modifications, characterized by decreased free thiols, robust induction of protein persulfidation, and comparatively modest changes in sulfenylation. These alterations are accompanied by increased intracellular hydrogen sulfide levels, supporting the involvement of reactive sulfur species in the cellular response to DNA damage. Proteome-wide analyses revealed that cysteine oxidative modifications preferentially target proteins involved in central metabolism, nucleotide biosynthesis, and genome maintenance. Consistent with these observations, MMS-induced genotoxic stress promotes metabolic adaptation characterized by increased mitochondrial respiration, elevated ATP production, and mitochondrial morphological remodeling, linking bioenergetic adaptation to redox regulation. Importantly, perturbation of intracellular redox balance using N-acetylcysteine compromises survival under DNA-damaging conditions, supporting a functional role for redox signaling during the DDR. Finally, MMS treatment also induces protein persulfidation in mammalian cells. Moreover, exposure to etoposide, a mechanistically distinct genotoxic agent that induces DNA double-strand breaks through topoisomerase II inhibition, showed a similar trend, suggesting that protein persulfidation may not be restricted to alkylation-induced DNA damage. Together our findings identify protein persulfidation as a prominent component of the redox response to DNA damage and provide new insight into the functional interplay between mitochondrial metabolism, cysteine-based redox regulation, and genome maintenance.

Oxidation-Reduction↗
PubMed2025

Biochemical and Structural Analyses of the Tardigrade DNA-Damage Suppressor Protein, Dsup.

Tardigrades are extremophiles that withstand harsh environments through unique molecular strategies. One such strategy involves Damage Suppressor (Dsup), a protein shown to protect cells from radiation-induced DNA damage. Little is known about the biochemical and structural characteristics of Dsup that lead to DNA protection. To gain insight into the mechanism of DNA protection by Dsup, we examined its fundamental biochemical and structural properties using mass photometry, biolayer interferometry, small-angle X-ray scattering, and microfluidic modulation spectroscopy. We found that Dsup is largely intrinsically disordered and binds DNA with high affinity via a multi-valent interface. This interaction induced conformational changes in both Dsup and the DNA, suggesting a potential structural mechanism of its DNA protection ability. We propose that Dsup alters DNA structure, possibly by partially unwinding it, to reduce its susceptibility to damage. These findings offer new insights into how a disordered protein such as Dsup functions as radioprotectants in extreme environments.

Tardigrada↗
PubMed2026

Vimentin loss inhibits DNA damage responses and promotes cancer cell survival.

Vimentin intermediate filaments are a hallmark of aggressive tumours and are widely linked to invasion and EMT, yet how vimentin-dependent mechanics shape genome maintenance and therapy response is unclear. Here we show that vimentin, particularly under compressive load, promotes DNA repair competence. In contrast, vimentin-negative cells show impaired DNA damage sensing and downstream signaling, ultimately leading to decreased apoptosis and promoting cell survival under genotoxic stress at the expense of genomic stability. Using controlled cell compression together with genetic and pharmacological perturbations, we find that loss of vimentin in glioblastoma cells limits the expression and activity of core repair pathways because of induced nuclear mechanical compression. Relieving nuclear compression restores DNA damage accumulation and repair kinetics. Functionally, suppression of DNA damage responses enhances survival after clinically relevant DNA-damaging treatments, including temozolomide, X-Ray radiation and cell invasion through tight spaces. These findings invert the prevailing view that vimentin's contribution to tumour progression stems from enhanced migration and identify a mechanochemical vimentin-nucleus axis that tunes DNA damage responses to favor therapy tolerance and genome evolution.

Journal Article↗
PubMed2025

Candida glabrata replicating within macrophages experiences amino acid deprivation, DNA damage, and chromosome instability.

Macrophages, the central players of innate immunity, control invading microbes by encapsulating them inside the phagosome, a nutrient-poor, reactive oxidant species-rich organelle. Nevertheless, some microbes, including the opportunistic yeast pathogen Candida glabrata, noted for its karyotype diversity, rapid evolution of antifungal drug resistance, and lack of meiosis, can survive and even replicate inside macrophages. However, it is not fully understood how C. glabrata responds to macrophage engulfment, and it is unknown how this presumably DNA-damaging environment influences the pathogen's genome stability. In this study, we used comparative transcriptomics to identify amino acid starvation and DNA damage as conditions eliciting C. glabrata responses most similar to macrophage engulfment. Consistent with this, we found that C. glabrata intra-macrophage survival and replication require master regulator of amino acid biosynthesis GCN4 and functional DNA double-strand break repair. Furthermore, comet assays provided the first direct evidence for increased DNA breaks in intra-macrophage yeast, and pulse-field gel electrophoresis showed that chromosomal alterations occur frequently in macrophage-passaged C. glabrata. Interestingly, these alterations could not be resolved by long read DNA sequencing, suggesting that they involved highly complex repetitive regions. Finally, we identified several point mutations emerging during macrophage passaging and showed that among them, a frameshift in RME1 (repressor of meiosis in Saccharomyces cerevisiae), increased C. glabrata intra-macrophage fitness. Together, these analyses point to amino acid deprivation, reveal elevated DNA breakage and chromosome instability, and raise intriguing questions about the role of meiotic gene orthologs in C. glabrata persisting and replicating within macrophages.

Journal Article↗