SEARCH · PubMed Health

Results for “Genome instability”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2026

Genomic instability, postoperative recurrence and therapeutic vulnerabilities in resectable non‑small cell lung cancer (Review).

Resectable non‑small cell lung cancer (NSCLC) is managed largely according to anatomical stage, pathological risk and actionable driver alterations, yet these factors do not fully explain postoperative recurrence. Genomic instability may contribute to recurrence by promoting clonal diversification, intratumoral heterogeneity, occult dissemination, persistence of residual tumor cells, and immune escape. In the present review, chromosomal instability (CIN), copy‑number complexity, whole‑genome doubling, DNA repair defects, replication stress, and extrachromosomal DNA (ecDNA) were critically evaluated using a three‑axis translational framework encompassing biological consequences, potential clinical roles, and strength of evidence. Current evidence suggests that clonal diversity and copy‑number complexity have the clearest near‑term prognostic rationale. By contrast, CIN and whole‑genome doubling are supported more strongly by evolutionary and mechanistic rather than prospective clinical evidence. Defects in DNA repair, replication stress, and ecDNA represent potential therapeutic vulnerabilities, but their clinical relevance remains to be established. To date, no treatment‑predictive biomarkers based on genomic instability have been identified for resectable NSCLC. Direct clinical evidence linking any specific genomic instability feature to the presence or longitudinal dynamics of postoperative molecular residual disease (MRD) remains limited. Postoperative circulating tumor DNA‑defined MRD provides prognostic information more directly related to residual disease but remains assay‑dependent and should not be considered a genomic‑instability phenotype. Therefore, features of genomic instability should remain investigational and should not replace established clinical, pathological, or molecular decision‑making. Their near‑term value lies in refining biological risk models and generating testable hypotheses for biomarker‑defined perioperative trials.

Humans↗

PubMed2025

Human Placental Genomic Instability Predicts Adverse Pregnancy Outcomes.

Preeclampsia is a leading cause of pregnancy-related death, accounting for over 50,000 maternal and 500,000 fetal deaths worldwide each year1-4. Preeclampsia has been linked to confined placental mosaicism, which underscores a potential role of placental genomic instability in driving adverse pregnancy outcomes. Here, using bulk RNA sequencing from 59 preeclamptic and 53 normotensive pregnancies, we explored somatic genomic instability and hypoxia with respect to clinical maternal-placental-neonatal outcomes. We found that genomic instability increased the probability of delivering at an earlier gestational age with a diagnosis of preeclampsia, maternal vascular malperfusion placental lesions, and small for gestational age neonates. Notably, genomic instability and hypoxia are predictive biomarkers for all three adverse pregnancy outcomes. In an induced pluripotent stem cell-derived trophoblast stem cell model, we observed increased genomic instability in trophoblast stem cells obtained from placentas demonstrating maternal vascular malperfusion with preeclampsia. Additionally, increased genomic instability correlated with reduced extravillous trophoblast invasion, implicating a functional role for genomic instability. These findings provide promising insights into the underlying mechanisms of genomic instability in the placenta which may be useful biomarkers for early clinical diagnosis of placental injury underlying preeclampsia.

Journal Article↗

PubMed2025

Characterization of oncohistone H2B variants in Schizosaccharomyces pombe reveals a key role of H2B monoubiquitination deficiency in genomic instability by altering gene expression.

Various amino acid substitutions commonly occur at one residue of a histone in human cancers, but it remains unclear whether these histone variants have distinct oncogenic effects and mechanisms. Our previous modeling study in the fission yeast Schizosaccharomyces pombe demonstrated that the oncohistone mutants H2BG52D, H2BD67N, and H2BP102L cause the homologous recombination defects and genomic instability by compromising H2B monoubiquitination (H2Bub). However, it is unknown whether other amino acid changes at the H2B-Gly52/Asp67/Pro102 residues influence H2Bub levels and whether they cause genomic instability by altering H2Bub-regulated gene expression. Here, we construct diverse oncomutants at the sole H2B gene htb1-Gly52/Asp67/Pro102 sites in S. pombe and study their impacts on genotoxic response, H2Bub levels, and gene expression. Interestingly, the oncomutants htb1-G52D, htb1-D67N, and htb1-P102L exclusively exhibit significant genotoxic sensitivity, reduced H2Bub levels, and altered gene expression. These defects can be rescued by restoring H2Bub levels with the deletion of the H2B deubiquitinase ubp8+. These strong genetic correlations suggest that H2Bub deficiency plays a determinant role in the genomic instability of htb1-Gly52/Asp67/Pro102 oncomutants and that the alteration of gene expression due to reduced H2Bub levels is a novel mechanism underlying the genomic instability caused by htb1-G52D, htb1-D67N, and htb1-P102L oncomutations.

Schizosaccharomyces↗

PubMed2025

Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.

Polyploid Giant Cancer Cells (PGCCs) occur across multiple cancer types and are associated with therapy resistance, genome instability, disease progression, and metastasis. PGCCs can grow through endocycles, a variant cell cycle of alternating Growth (G) and DNA Synthesis (S) phases without cell division. Unlike programmed endocycles that occur during normal tissue development, PGCCs switch from mitotic cycles to unscheduled endocycles in response to stress. PGCCs can subsequently return to error-prone divisions which generate aneuploid daughter cells that contribute to disease progression. However, the regulation of PGCC cell cycles and contributions to cancer are still being defined. Filling this knowledge gap will lead to the development of improved cancer therapies. In this study, we used a molecular-genetic system in the model organism Drosophila melanogaster to examine how oncogenes interact with unscheduled endocycles in vivo. We found that several oncogenes promote bypass of an endocycle arrest, resulting in increased polyploid cell size and DNA content. The extent of this increased growth was dependent on the type of oncogenic mutation. When these polyploid cells returned to division, RasG12V promoted continued divisions of polyploid daughter cells with elevated genome instability. RasG12V expression during transient endocycles and subsequent divisions also induced expression of a matrix metalloprotease and a Wnt pathway ligand. Importantly, RasG12V with transient endocycles enhanced the growth of large, neoplastic tumors. These findings indicate that oncogenic mutations can synergize with transient, unscheduled endocycles to promote tumorigenesis with important broader implications for cancer prognosis and therapies.

Animals↗

PubMed2026

The interplay of epigenetic remodelling and transposon-mediated genomic instability in ageing and longevity.

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications and the reactivation of transposable elements (TEs). TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

Aging↗

PubMed2025

Lamin A/C loss promotes R-loop-mediated genomic instability and poor survival in small-cell lung cancer.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [W. Xie et al., Curr. Biol. 26, 2651-2658 (2016)]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [S. Graziano et al., Nucleus 9, 258-275 (2018)]. Here, we define a mechanistic role for LMNA in preserving genome stability in small-cell lung cancer (SCLC), a malignancy marked by extreme genomic instability [N. Takahashi et al., Cancer Res. Commun. 2, 503-517 (2022)]. LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA deficiency disrupts nuclear pore complex organization, specifically reducing phenylalanine-glycine (FG)-nucleoporin incorporation, resulting in impaired RNA export and nuclear retention of RNA. LMNA expression is repressed by EZH2 and reexpressed during SCLC differentiation from neuroendocrine (NE) to non-NE states, and low LMNA levels correlate with poor clinical outcomes. These findings establish LMNA as a key regulator of nuclear transport and genome integrity, linking nuclear architecture to SCLC progression and therapeutic vulnerability.

Lamin Type A↗

PubMed2026

Coagulation activation is associated with genomic-instability-related features in TP53-mutated AML and MDS: routine laboratory patterns beyond classical disseminated intravascular coagulation.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a serious complication of acute myeloid leukemia (AML) associated with poor prognosis. In TP53-mutated AML and myelodysplastic syndrome (MDS), however, the classical ISTH criteria rarely identify overt DIC, although bleeding and thrombotic complications are well documented in acute leukaemia. We hypothesized that these patients exhibit a lower-grade, subclinical coagulation activation that is associated with the underlying genomic-instability-related features of TP53-mutant disease. METHODS: We retrospectively analyzed 107 consecutive patients with TP53-mutated AML (n = 52) or high-risk MDS (MDS, n = 55), median age 65 years, diagnosed and initially evaluated at our centre between 2018 and 2025. Seven routine coagulation markers and 46 co-mutated genes were evaluated for associations with overall survival (OS) using univariate and multivariable Cox regression, continuous dose-response modeling, and unsupervised k-means clustering. Internal validity was assessed by 1000 bootstrap resamples. RESULTS: Overt DIC according to ISTH criteria was rare (15%). Subclinical activation was common: 50% of patients had a D-dimer ≥1 μg/mL, 41% a fibrinogen ≥4 g/L, and 29% an INR ≥1.2. In univariate analysis, D-dimer, fibrinogen, INR, prothrombin time, and activated partial thromboplastin time were each associated with OS (HR 1.33-1.38 per SD; all p < 0.05). Complex karyotype correlated with higher D-dimer (median 1.39 vs. 0.60 μg/mL, p = 0.022) and fibrinogen (3.91 vs. 2.53 g/L, p = 0.007), while TP53 variant allele frequency (VAF) showed modest positive correlations with D-dimer (ρ = 0.21), INR (ρ = 0.27), and PT (ρ = 0.27; all p < 0.05). Clustering identified three coagulation phenotypes: Silent (51%), Thrombo-inflammatory (31%), and Consumption-like (18%), showing a graded but statistically non-significant gradient in molecular features and a stepwise decline in median OS (14, 10 and 8 months; log-rank p = 0.041). After adjustment for complex karyotype, TP53 VAF, and favorable co-mutation count, the Consumption-like phenotype was associated with a non-significant increased risk (HR 1.83, 95% CI 0.92-3.65, p = 0.084), whereas favorable co-mutation pathways remained independently protective (HR 0.56, 95% CI 0.35-0.90, p = 0.016). CONCLUSION: In TP53-mutated AML/MDS, coagulation activation intensity is associated with the degree of genomic instability. The three phenotypes may add biological resolution beyond classical DIC and cytogenetic risk groups, but represent laboratory patterns rather than validated bleeding or thrombosis prediction tools. However, after accounting for genomic features, phenotypes were not independent predictors of outcome, with complex karyotype, TP53 VAF, and favorable co-mutation count driving prognosis. Because treatment intensity and other clinical confounders were not available, these survival associations are hypothesis-generating. Coagulation profiling remains inexpensive, widely accessible, and offers a practical window into disease biology that warrants prospective validation.

TP53↗

PubMed2025

Lamin A/C Deficiency Drives Genomic Instability and Poor Survival in Small-Cell Lung Cancer through Increased R-loop Accumulation.

Lamin A/C (LMNA), a key component of the nuclear envelope, is essential for maintaining nuclear integrity and genome organization [1]. While LMNA dysregulation has been implicated in genomic instability across cancer and aging, the underlying mechanisms remain poorly understood [2]. Here, we investigate LMNA's role in small-cell lung cancer (SCLC), a highly aggressive malignancy characterized by extreme genomic instability [3, 4]. We demonstrate that LMNA depletion promotes R-loop accumulation, transcription-replication conflicts, replication stress, DNA breaks, and micronuclei formation. Mechanistically, LMNA loss disrupts nuclear pore complex distribution, reducing phenylalanine-glycine (FG)-nucleoporin incorporation and impairing RNA export efficiency. Furthermore, we show that LMNA expression is epigenetically repressed by EZH2 during SCLC differentiation from neuroendocrine (NE) to non-NE states. Clinically, low LMNA levels correlate with significantly worse survival in SCLC patients. These findings uncover a novel role for LMNA in safeguarding genome integrity and shaping tumor heterogeneity, with broad implications for cancer and aging.

Biological Sciences↗

PubMed2026

Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability.

p53 plays a central role in the DNA damage response, inducing repair, cell-cycle arrest or apoptosis. Its loss is associated with replication stress and genomic instability. While several underlying mechanisms were suggested, the primary triggers of catastrophic genomic events like chromothripsis, a known driver of tumorigenesis linked with p53 loss, are still unclear. Using p53-depleted epithelial cells and fibroblasts, as well as patient-derived fibroblasts with germline p53 variants that spontaneously undergo chromothripsis, we found that p53 loss causes hypertranscription and increased nucleotide consumption. The resulting nucleotide shortage induces replication stress, causing telomere dysfunction, micronuclei formation, and chromothripsis. These effects were rescued by nucleoside supplementation or normalization of transcription levels, demonstrating a causal link between transcriptional activity, nucleotide availability, and genome stability. Emerging chromothriptic clones displayed restored DNA replication, telomere stabilization, and extrachromosomal DNA, suggesting key features that support clonal selection. We identify nucleotide pool homeostasis as a critical p53 function that suppresses replication stress, prevents chromothripsis, and protects against early tumorigenesis.

Genomic Instability↗

PubMed2026

Beyond Morphology: Reframing Lymph-Node Metastasis Prediction Through Clonal Ecology-Decades-Long Genomic Instability and Polyclonal-to-Monoclonal Transitions as the Missing Dimension in Cancer.

Recent whole-genome, lineage-tracing, single-cell, and spatial studies have reshaped our understanding of tumor evolution, revealing that cancers can arise from polyclonal populations, undergo decades-long genomic instability before clinical detection, and progress through dynamic changes in subclonal composition, cellular state, and ecological organization. These findings challenge the assumption underlying morphology-based prediction models that metastatic risk can be inferred from static histological features alone. Here, we revisit lymph-node metastasis prediction in colorectal cancer through clonal ecology, integrating computational pathology with evolutionary oncology. Drawing on the subclonal switchboard model proposed in 2012 and subsequent artificial intelligence (AI)-enabled approaches for tracking dominant and dormant subclones, we synthesize evidence that metastatic potential reflects clonal ancestry, evolutionary timing, spatial niche architecture, cellular plasticity, intercellular interactions, dormancy, and treatment-driven shifts in subclonal fitness. We define five complementary methodological pillars for operationalizing clonal ecology: single-cell transcriptomics for resolving rare subclones, evolutionary trajectories, and adaptive cell states; lineage tracing and phylogenetics for reconstructing clonal ancestry and divergence; spatial transcriptomics and genomics for mapping subclonal geography and tumor-stromal-immune interactions; longitudinal liquid biopsy surveillance for monitoring residual disease, clonal turnover, and emerging resistance; and AI-enabled multimodal integration for connecting histopathology, genomics, spatial biology, and longitudinal data into predictive ecological-state models. Multiple-instance learning and pathology foundation models provide scalable computational foundations for evolution-aware prediction. Translationally, dormant subclones represent actionable reservoirs of recurrence. A longitudinal clinical and experimental study of KMT2A-rearranged acute myeloid leukemia further supports central predictions of the subclonal switchboard framework by demonstrating treatment-associated shifts in subclonal dominance, persistence of cryptic adaptive programs, and ecological rewiring during resistance and relapse. We propose clonal ecology as a measurable dimension for extending morphology-driven prediction toward integrative models that anticipate evolutionary transitions, identify therapeutic windows, and proactively constrain adaptive tumor ecosystems before resistant or metastatic subclones achieve clinical dominance.

Humans↗

PubMed2026

G-quadruplex structures as regulators of cellular processes and drivers of genome instability in cancer.

G-quadruplexes (G4s) are essential regulatory structures whose biological functions are inseparable from their potential to destabilize the genome. They play critical roles in transcription, replication and chromatin architecture, yet they also contribute to the genomic instability that fuels cancer. This dual role is an inherent consequence of where G4s form in the genome. G4s are enriched at highly active regulatory regions, including promoters, replication origins and topologically associated domain boundaries, where their controlled formation and resolution by helicases and topoisomerases support normal genome function. When this control is lost, the same features that make G4s functional become harmful, leading to R-loop and G-loop accumulation, replication fork stalling and increased conflicts between transcription and replication. Topoisomerase activity, which normally relieves supercoiling stress, can instead generate the DNA double-strand breaks that characterize cancer genomes. Persistent G4 structures also promote micronuclei formation and cytoplasmic DNA accumulation, activating the cGAS-STING innate immune signaling pathway. Here, we discuss these mechanisms and present pan-cancer genomic analyses showing that these processes operate broadly across human tumors. Therapeutically targeting G4s requires balancing their essential regulatory roles with their pathological effects. Understanding this tension is therefore essential for exploiting G4s as therapeutic targets across cancer types.

DEAH-box helicases↗

PubMed2026

Tissue-based genomic instability markers for predicting malignant transformation in oral leukoplakia and proliferative verrucous leukoplakia: a systematic review.

OBJECTIVES: Although several biomarkers have been described for predicting malignant transformation in oral leukoplakias (OLs) and proliferative verrucous leukoplakias (PVLs), no systematic review has comprehensively evaluated tissue-based genomic instability markers. This review aimed to evaluate the evidence for these markers and their potential role in biomarker panel development. METHODS: A systematic review across PubMed, Embase and Cochrane Library was performed to identify studies evaluating the differences in tissue-based genomic markers between OL and PVL patients with and without malignant transformation. RESULTS: 34 observational studies comprising 3,237 patients were included, and genomic aberrations were categorised into DNA-level, chromosomal, and gene-specific alterations. For studies on OLs, DNA-level and chromosomal markers for which individual studies reported associations with malignant transformation included aneuploidy, impaired DNA repair capacity, loss of heterozygosity, chromosomal instability, and copy number alterations. Multiple gene-specific alterations also showed associations (e.g., TP53, MKI67, FGFR1), but findings varied across studies. The genomic markers of PVLs differed substantially, with fewer consistent predictors found. No meta-analysis was performed as all included studies were observational. CONCLUSIONS: Genomic instability across multiple levels contributes to malignant transformation, and represents a promising biological framework for predicting malignant transformation for OLs. While no single marker reliably demonstrates sufficient predictive performance, the integration of complementary genomic alterations with clinical and histopathological risk factors may provide a basis for the development of robust multi-marker panels. Future prospective studies using standardised detection methods and multivariable prediction models are required before clinical implementation. SYSTEMATIC REVIEW REGISTRATION: identifier CRD42024585830.

carcinoma↗

PubMed2025

Dihydroxyacetone decreases the dATP pool, inducing replication stress and genomic instability in BEAS-2B cells.

Dihydroxyacetone (DHA), found in sunless tanning products and electronic cigarette aerosol, induces cytotoxic and genotoxic effects in cells. Studies across skin and systemic models demonstrated that DHA induces cell cycle arrest and mitochondrial stress, but its impact on replication is unknown. We investigated DHA exposure effects on lung epithelial BEAS-2B cells to determine if it induces replication stress and genomic instability. Acute DHA exposure generated oxidative stress, triggering 53BP1 foci formation 24 and 48 h after exposure. Evaluation of DNA damage response showed increased levels of pChk2 and pP53, demonstrating activation of double-strand break response. Using a DNA fiber assay, we observed decreased replication fork progression, which coincided with increased micronuclei formation. Removal of DHA from cell media partially alleviated the replication stress, similar to the removal of hydroxyurea, suggesting a reversible effect. Given DHA's incorporation into glycolytic pathways and induction of mitochondrial stress, we examined its effects on nucleotide biosynthesis and pool composition. DHA exposure reduced ribonucleotide reductase (RRM1/2) expression and specifically depleted dATP pools after 48 h. We confirmed that dATP depletion drives replication stress by supplementing cells with adenine during DHA exposure, which decreased DNA lesions, reduced damage signaling, and restored replication. Adenine supplementation also partially rescued DHA-induced cytotoxicity and micronuclei formation. These data demonstrate that DHA-induced DNA damage and dATP pool depletion cause replication stress in BEAS-2B cells, providing new information on DHA's genotoxic mechanism. The inability of adenine to completely rescue micronuclei formation also suggests additional mechanisms of action that impact mitosis, requiring further investigation.

Humans↗

PubMed2025

Reproductive Isolation due to Divergent Ecological Selection Is Accompanied by Vast Genomic Instability in Experimentally Evolved Yeast Populations.

Populations evolving independently in divergent environments accumulate genetic differences and potentially evolve reproductive isolation as a by-product of divergence. The speed and mechanisms underlying this process are difficult to investigate because we rarely get the opportunity to witness them in natural settings, and histories of selection and gene flow between populations are often unknown. Here, we experimentally evolved yeast for 1000 generations of evolution in both divergent and parallel environments. At regular time points during experimental evolution, we made crosses between parallel- and divergent-evolving populations to measure postzygotic reproductive isolation (gamete viability). We used whole genome population sequencing to determine the mutational load, the number and types of structural variation, and other genomic features of the parent, F1 and F2 intraspecific hybrids. We found evidence for large-scale phenotypic and genome-wide differentiation in response to divergent laboratory selection. Divergent-selected populations produced hybrids with reduced gamete viability-a classic signature of postzygotic reproductive isolation in the form of hybrid breakdown. Parallel-selected populations, on the other hand, remained more reproductively compatible (with exceptions). We found that F2 hybrid genomes contained vast genomic instability, that is, new structural variants (especially insertions, deletions and interchromosomal translocations) that were not observed in parent and F1 genomes, which is likely a result of chromosome missegregation and recombination errors in hybrid meiosis. Our results provide phenotypic and genomic evidence that partial reproductive isolation evolved due to adaptation to divergent environments, consistent with predictions of ecological speciation theory.

Reproductive Isolation↗

PubMed2024

Surviving without BRCA2: MLH1 gets R-looped in to curtail genomic instability.

While breast cancer 2 (BRCA2) loss of heterozygosity (LOH) promotes cancer initiation, it can also induce death in nontransformed cells. In contrast, mismatch repair gene mutL homolog 1 (MLH1) is a tumor-suppressor gene that protects cells from cancer development through repairing mismatched base pairs during DNA mismatch repair (MMR). Sengodan et al., in this issue of the JCI, reveal an interplay between the 2 genes: MLH1 promoted the survival of BRCA2-deficient cells independently of its MMR function. MLH1 protected replication forks from degradation, while also resolving R-loops, thereby reducing genomic instability. Moreover, MLH1 expression was regulated directly by estrogen, shedding light into the hormone-responsive nature of many BRCA2 mutant breast cancers. These results provide important insight into the genetics that drive the initiation of BRCA2-mutated breast cancers.

Humans↗

PubMed2026

Comet assay analysis of multigenerational genomic instability (F0-F2) in Aedes aegypti exposed to gamma radiation in Sterile Insect Technique.

The use of irradiation in the Sterile Insect Technique (SIT) is a sustainable and environmentally friendly strategy for controlling Aedes aegypti populations by the release of sterile males. However, the potential toxic effects of radiation on mosquito genetic material, as well as the heritability of such damage, remain insufficiently understood. In this study, we evaluated gamma radiation-induced DNA damage (20, 30, 40, and 50 Gy) in male pupae (F0 generation) and assessed the persistence of these effects in subsequent generations (F1 and F2) using the comet assay in hemocytes. In the parental generation, a significant dose-response relationship was observed, with increasing radiation doses associated with higher damage index and damage frequency (p < 0.05). In the F1 generation, both larvae and adults exhibited significantly greater DNA damage than the control group, particularly at doses of 30 and 40 Gy, supporting the inheritance of radiation-induced genomic instability. In the F2 generation, genotoxic effects were attenuated, although residual damage remained detectable in adults, suggesting partial recovery of genomic stability, possibly influenced by DNA repair mechanisms and/or selective pressures. No viable offspring were obtained at 50 Gy, confirming the sterilizing efficacy of higher doses. Integration of comet assay results with micronucleus data and reproductive parameters reinforces the association between DNA damage, mutagenic effects, and reduced fertility. These findings indicate that radiation-induced genotoxic effects may persist beyond the irradiated generation but tend to decline across generations. Overall, this study provides insights into the balance between achieving sterility and preserving biological quality in SIT programs, contributing to optimizing radiation doses and enhancing the safety and efficacy of vector control strategies.

Comet assay↗

PubMed2026

When R-Loops Go Awry: Genome Instability and Neurological Diseases.

The basic structure of DNA is a double helix formed by base pairing between complementary strands. However, during transcription, RNA hybridizes with the template DNA, whereas the complementary DNA strand becomes displaced and remains unpaired. This process forms a DNA-RNA hybrid structure known as an R-loop; similar structures can also occur in a non-co-transcriptional manner. In recent years, R-loops have been reported to be involved in various cellular functions. However, when not properly regulated, they can compromise genomic DNA stability. R-loops play roles in gene expression, DNA replication, and transcription termination. Dysregulation of R-loop homeostasis has been implicated in various human diseases, including neurological diseases. In this review, we discuss the physiological and pathological roles of R-loops, their related regulatory mechanisms controlling their formation and resolution, and their association with neurological diseases.

Humans↗

PubMed2025

PUMA-induced apoptosis drives bone marrow failure and genomic instability in telomerase-deficient mice.

Bone marrow failure is a severe complication of human telomere biology disorders and predisposes individuals to secondary leukemia. A deeper understanding of this process could offer significant clinical benefits. Using a preclinical mouse model deficient in the RNA component of the telomerase (mTerc), we demonstrate that bone marrow failure results from excessive apoptosis, predominantly mediated by the pro-apoptotic p53 target PUMA. Genetic ablation of Puma alleviates hematological phenotypes and reduces the risk of lethal bone marrow failure while preserving genomic stability. Mechanistically, PUMA deficiency decreases the sensitivity of hematopoietic cells to lethal stressors, including critically short telomeres. As a consequence, reduced compensatory turnover of hematopoietic progenitors slows down telomere shortening at the population level, delays stem cell exhaustion, and diminishes the acquisition of somatic mutations - ultimately preventing neoplastic transformation. Elevated expression of both p53 and PUMA is also observed in the bone marrow from patients with telomere biology disorders. While apoptosis resistance is traditionally associated with malignant transformation, our findings provide evidence that selective inhibition of PUMA-mediated apoptosis may represent a viable therapeutic strategy to prevent or delay leukemic transformation in this patient population.

Animals↗