Genome Integrity Research Articles (Page 1)

Abstract Introduction Integration of genomics into clinical practice across all sectors, from primary care to specialist and tertiary care, is part of the Genomics strategy for NHS England (NHSE) [1]. Historically pharmacogenomics has been seen as relating only to specialised areas such as oncology and HIV. However, pharmacogenomic information is increasingly available in standard medicines information sources such as the Summary of Manufacturers Product Characteristics (SmPC), and requirements or recommendations for genomic testing prior to prescribing are becoming more common. To embed these requirements into everyday practice, it would be prudent to incorporate them into local prescribing formularies and medicines governance processes. Aim This project’s aim was to determine if actionable genomic information is included in Blueteq NHSE High-Cost Drug forms and local formularies, in line with NHSE plans to integrate genomics into Medicines Optimisation. Methodology Ethical approval was not required as no patient records were accessed and no changes made to patient care. NHS high-cost-drug-list-23-24-v19 [2] and an informal list of commonly prescribed medicines with pharmacogenomics mentioned in their SmPC were interrogated for gene-related prescribing recommendations. Formularies from three large ICBs across NHS Central and South Genomics region were compared against the combined list to assess pharmacogenomic coverage. Descriptive statistical analysis in Excel using frequency and proportion to assess actionable gene data across drug types and formularies. Results 228 of 506 reviewed drugs (45%) had associated actionable genes. 135 of the 228 drugs (59%) were high-cost drugs and the rest commonly prescribed drugs (41%). 52 of the 228 drugs (23%) with actionable gene recommendations were for cancer indications. 125 individual genes or gene targets were identified, with the cytochrome P450 cluster being the most frequent, associated with 43/228 drugs (19%), followed by G6PD in 26/228 (11%). 62 of the 135 high-cost drugs (46%) had pharmacogenomic testing requirements in the associated Blueteq form. 90 of the 93 commonly prescribed drugs with actionable genetic recommendations had no reference to pharmacogenomics in the three ICB formularies reviewed. The remaining 3 drugs, capecitabine, 5-fluorouracil and mavacamten included relevant pharmacogenomic information in one of the three formularies. Discussion This project found that pharmacogenomic requirements and available information was poorly reflected in three ICB formularies. This was particularly the case for commonly prescribed medicines. Barriers to inclusion of this information potentially include current testing infrastructure and availability, lack of national guidelines and poor knowledge about pharmacogenomics. Study limitations include local Trust guidance not being referenced in formularies. The development and inclusion of a standardised ‘genomic testing recommended’ tag in NHS formularies might be a useful system-wide development [3]. Pharmacogenomic information will increasingly become part of rational prescribing, for new targeted and precision medicines, and common medicines. The use of genomic information to guide prescribing practice has the potential to improve effectiveness and reduce adverse effects, not only in specialised care, but also in general practice. We consider that including reference to pharmacogenomic tests within local formularies, as these become available, will further the cause of integration of genomics into everyday Medicines Optimisation.

Background Gaucher disease (GD) is characterized by significant phenotypic heterogeneity, even among patients with identical GBA1 genotypes, suggesting the role of genetic and/or epigenetic modifiers. The enzymatic defect and pathological accumulation of glucosylceramide (GlcCer) lead to chronic metabolic inflammation, providing ample opportunities for interaction with other biological pathways to influence disease expression. Herein, we developed a model of precision medicine in this prototype single-gene disorder. Methods This study leveraged a well-characterized, longitudinally followed cohort of GD patients from a major tertiary care center, integrating whole-exome sequencing (WES) with detailed clinical information. We applied a precision medicine framework centered on four components—clinical reasoning, deep phenotyping, genomic integration, and individualized therapy—to a subset of patients (n = 17) who presented with complex phenotypes deviating from the classical GD presentation and/or were a priori suspected of harboring a second genetic disorder. Results Of 275 patients, 17 (6.2%) presented with atypical phenotypes not fully explained by GD. WES revealed additional genetic diagnoses, including hereditary hemochromatosis-associated variants (n = 5), familial Mediterranean fever (n = 4), homozygous MSH6 mutation-associated hereditary cancer predisposition (n = 2), and autosomal dominant polycystic kidney disease (ADPKD) (n = 2). Conclusion The presence of concurrent genetic disorders in a subset of GD patients has the potential to modify clinical presentation, impact disease trajectory, and introduce additional complexities in clinical management. This study contributes to advancing precision medicine strategies that aim to optimize patient outcomes. Future research into genetic and epigenetic modifiers of GD will further refine this framework and enhance individualized therapeutic approaches.

An independent association between insulin resistance and cancer has been consistently reported in humans. Patients with cancer display insulin resistance or its clinical manifestations, and this metabolic adaptation precedes the clinical diagnosis of cancer. Insulin resistance in cancer patients is associated with a metabolic switch from oxidative metabolism toward glycolysis that spares oxygen to be used in anabolic processes and facilitates the fast production of energy and intermediate metabolites required for the rapid proliferation of cancer cells. In malignant cells, glucose consumption via glycolysis occurs under normoxic conditions (aerobic glycolysis). Pathogenic mechanisms underlying insulin resistance in cancer patients include hypoxia-inducible factor-1 upregulation and overproduction of cytokines, such as interferon, interleukin-6, interleukin-18, and interleukin-1β. Deficit of 2-oxoglutarate (α-ketoglutarate) has been detected in cancer cells and may facilitate hypoxia-inducible factor-1 assembly and activity. Overproduction of cytokines in cancer patients follows activation of the immune system by abnormal nucleic acid variants. Anomalous DNA or RNA structures are recognized by immune sensors and stimulate signaling pathways that ultimately increase cytokine production. Likewise, interferon overproduction occurs in congenital disorders that feature ineffectively repaired DNA lesions, such as Werner syndrome, Bloom syndrome, mutations in DNA polymerase-δ1, and ataxia telangiectasia. These diseases cause simultaneous insulin resistance and a high tendency to develop cancer, highlighting the relationship between the two processes. Defectively repaired DNA injury endangers genomic integrity, predisposing to cancer, and activates the immune system to increase interferon production and subsequent insulin resistance. Hypoxia-inducible factor-1 and cytokines induce insulin resistance by suppressing peroxisome proliferator-activated-γ in the subcutaneous adipose tissue.

Poly (ADP-ribose) polymerase 1 (PARP1) is an important enzyme that plays a central role in the DNA damage response, facilitating repair of single-stranded DNA breaks via the base excision repair (BER) pathway and thus genomic integrity. Its therapeutic relevance is compounded in breast cancer, particularly in BRCA1 or BRCA2 mutant cancers, where compromised homologous recombination repair (HRR) leaves a synthetic lethal dependency on PARP1-mediated repair. This review comprehensively discusses the recent advances in computational chemistry for the discovery of PARP1 inhibitors, focusing on their application in breast cancer therapy. Techniques such as molecular docking, molecular dynamics (MD) simulations, quantitative structure–activity relationship (QSAR) modeling, density functional theory (DFT), time-dependent DFT (TD-DFT), and machine learning (ML)-aided virtual screening have revolutionized the discovery of inhibitors. Some of the most prominent examples are Olaparib (IC50 = 5 nM), Rucaparib (IC50 = 7 nM), and Talazoparib (IC50 = 1 nM), which were optimized with docking scores between −9.0 to −9.3 kcal/mol and validated by in vitro and in vivo assays, achieving 60–80% inhibition of tumor growth in BRCA-mutated models and achieving up to 21-month improvement in progression-free survival in clinical trials of BRCA-mutated breast and ovarian cancer patients. These strategies enable site-specific hopping into the PARP1 nicotinamide-binding pocket to enhance inhibitor affinity and specificity and reduce off-target activity. Employing computation and experimental verification in a hybrid strategy have brought next-generation inhibitors to the clinic with accelerated development, higher efficacy, and personalized treatment for breast cancer patients. Future approaches, including AI-aided generative models and multi-omics integration, have the promise to further refine inhibitor design, paving the way for precision oncology.

One of the main causes of the global disease burden is psychiatric disorders. However, due to the complex relationships between genetic, epigenetic, environmental, and neurological factors, diagnosing and treating these conditions remains challenging. Precision psychiatry, driven by multi-omics and artificial intelligence (AI), offers a novel approach to understanding mental health conditions and developing personalized treatments. This review examines the contributions of genome integration, transcriptomics, epigenomics, proteomics, metabolomics, and microbiome studies to psychiatric research and diagnosis. The area has changed as a result of recent developments in AI, particularly in machine learning and deep learning, combined with information from patient-reported outcomes, electronic health records, and neuroimaging. AI models facilitate the creation of customized treatment regimens, enhance pharmacogenomic predictions, and aid in the identification of biomarkers. Furthermore, the interpretability issues of these models are addressed by the emergence of explainable AI (XAI), which facilitates more transparent healthcare choices. The broad clinical application of precision psychiatry is, however, hindered by several challenges, including the difficulty in integrating multi-omics data, ethical concerns about the use of AI in mental health, and the need for thorough validation across diverse populations. Computational biologists, neuroscientists, psychiatrists, and clinicians from other disciplines must collaborate to address these challenges and develop scalable, reliable, and ethically sound frameworks for precision medicine in psychiatry. This study lays the groundwork for future research and clinical practice by highlighting the potential for integrating AI and multi-omics technology to revolutionize psychiatric care. Precision psychiatry can transition from a trial-and-error method to a tailored and predictive one by utilizing sophisticated computational tools, ultimately improving patient outcomes and mental health treatment. This study is among the first comprehensive efforts to explore the integration of multi-omics and AI, especially XAI, within the context of precision psychiatry, establishing a translational model for tailored mental health treatment. Received: 25 April 2025 | Revised: 5 August 2025 | Accepted: 17 October 2025 Conflicts of InterestThe authors declare that they have no conflicts of interest to this work. Data Availability StatementThe data supporting the findings of this study are available upon request from the corresponding author. Author Contribution StatementOluwafikayo Seun Adeyemi-Benson: Conceptualization, Methodology, Software, Validation, Writing – original draft, Writing – review & editing.

Cold-adapted species display remarkable genomic resilience under prolonged freezing and thawing cycles that would be lethal to most organisms. This review synthesizes current knowledge on the molecular mechanisms of DNA damage response (DDR) and epigenetic regulation that collectively safeguard genome integrity in these organisms. We highlight key DNA repair pathways, including base excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR), and non-homologous end joining (NHEJ), that are activated during freeze–thaw stress to repair oxidative and strand break damage. Epigenetic regulators such as DNA methyltransferases (DNMTs), histone methyltransferases, and histone deacetylases (HDACs) dynamically remodel chromatin and modulate DDR signaling, facilitating efficient repair and transcriptional reprogramming during recovery. Comparative evidence from freeze-tolerant vertebrates, hibernating mammals, and polar fish underscores the conservation of these adaptive pathways across taxa. Integrating these insights provides a molecular network perspective (MNP) linking DDR and epigenetic mechanisms to environmental resilience, with potential applications in crop improvement and biotechnological adaptation strategies for extreme environments.

Insertions of large DNA sequences into the genome are broadly enabling for research and therapeutic applications. Large serine recombinases (LSRs) can mediate direct, site-specific genomic integration of multi-kilobase DNA sequences without a pre-installed landing pad, albeit with low insertion rates and high off-target activity. Here we present an engineering roadmap for jointly optimizing their DNA recombination efficiency and specificity. We combine directed evolution, structural analysis and computational models to rapidly identify additive mutational combinations. We further enhance performance through donor DNA optimization and dCas9 fusions, enabling simultaneous target and donor recruitment. Our top engineered LSR variants, superDn29-dCas9, goldDn29-dCas9 and hifiDn29-dCas9, achieve up to 53% integration efficiency and 97% genome-wide specificity at an endogenous human locus and effectively integrate large DNA cargoes up to 12 kb for stable expression in non-dividing cells, stem cells and primary human T cells. Rational engineering of DNA recombinases enables precise and efficient single-step genome insertion for diverse applications across gene and cell therapies.

BackgroundKidney transplantation is the preferred treatment for end-stage renal disease (ESRD), yet challenges persist in long-term graft survival and post-transplant complications. Genomic profiling, especially whole-exome sequencing (WES), offers new opportunities to personalize donor-recipient matching and predict transplant outcomes. This study aimed to explore the genetic landscape of both transplant recipients and donors using WES.MethodsThis prospective cohort study included 64 kidney transplant recipients (51 adults, 13 pediatric) and 61 donors in Kazakhstan. WES was performed to identify monogenic causes of ESRD, evaluate rejection-associated immune polymorphisms (31 SNPs), and screen for post-transplant risk using a 355-gene Transplant Morbidity Panel. Variants were classified following ACMG/AMP guidelines, and allele frequencies were compared to global reference datasets.ResultsAmong recipients, pathogenic/likely pathogenic variants were found in 15.4% of pediatric and 9.1% of adult cases, with additional variants of uncertain significance detected in 23.1% and 23.6%, respectively. WES identified monogenic nephropathies including Alport syndrome, cystinuria, and polycystic kidney disease. In donors, 13.1% carried variants associated with latent renal or systemic conditions despite no clinical manifestation at donation. The APOE p.Cys130Arg variant, linked to lipid dysregulation, was observed more frequently in recipients (allele frequency 0.17) than donors (0.09), though not statistically significant. Among the 31 SNPs evaluated, significant associations with acute rejection were observed for IL1B rs1143634 and TP53 rs1625895 under dominant models. IL1B carriers showed increased rejection risk (OR = 4.62, p = 0.039), whereas TP53 carriers appeared protected (OR = 0.058, p = 0.027). Given the limited number of rejection cases, these findings should be considered exploratory and require validation in larger cohorts. Additionally, 44.3% of recipients carried at least one pathogenic or likely pathogenic variant in the Transplant Morbidity Panel, particularly in genes related to malignancy, cardiomyopathy, and monogenic diabetes.ConclusionsThis study provides one of the first applications of WES in a Central Asian kidney transplant population. Findings highlight the prevalence of monogenic and comorbid risk variants in both recipients and donors and support the use of genomic screening for improving pre- and post-transplant care. The identification of immune-related SNPs and extra-renal findings further underscores the utility of WES for personalized transplant management. Integration of genomics into transplant workflows may help address the ongoing gap between clinical need and transplant outcomes, particularly in low-resource settings.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12882-025-04553-x.

Human papillomavirus type 16 (HPV16) E6 and E7 are oncogenic proteins that are overexpressed following viral genome integration into the chromosomal DNA of infected mucosal epithelial cells, contributing to viral immune evasion and carcinogenesis. Epithelial cells can shed large extracellular vesicles (LEVs) that may modulate immune responses. We hypothesise that LEVs shed from epithelial cells expressing E6 and E7 modulate CD8+ T cell priming by the skin-local antigen presenting cells, the Langerhans cells (LCs). LEVs were isolated from control and E6/E7-expressing murine epithelial PDV cells. PDV-E6/E7 cells shed threefold more LEVs than control PDV cells invitro. Murine LC 'like' cells were differentiated invitro, co-cultured with LEVs, and assessed for antigen presentation, co-stimulatory molecule expression and cytokine production. We found that LCs co-cultured with Ctrl-LEVs demonstrated enhanced TAP1-dependent CD8 T cell priming, which was associated with increased co-stimulatory molecule and IL-12 expression. LCs co-cultured with E6/E7-LEVs failed to enhance TAP-1-dependent T cell priming and suppressed IL-12 production despite upregulating MHC-1 and co-stimulatory molecule expression. Our results show that LC priming of T cells is enhanced following treatment with Ctrl-LEVs whereas LEVs from HPV16 E6/E7 expressing cells suppress LC function. Functional impairment of LC priming of T cells by E6/E7-LEVs released in the epithelium may contribute to viral persistence in HPV16-infected skin.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have attracted significant attention in triple negative breast cancer (TNBC) treatment. However, the acquired or de novo PARP inhibitor resistance limits treatment success. Ataxia telangiectasia and Rad3-related (ATR) regulates genome integrity, and thus, the aberrant activation of ATR could play a significant role in the pathogenesis of TNBC and be associated with PARPi resistance in especially homologous recombinant deficiency tumors. We aimed to assess the efficacy of ATR and PARP inhibitors combination in TNBC cells and the reversal of PARPi resistance in resistant cells. HCC1937 and HCC1937-R Talazoparib (TAL) resistant cells were treated with Elimusertib (ELI) alone as ATR inhibitor (ATRi) and ELI and TAL combination. Then, the cytotoxic, apoptotic and ATR based DNA damage response (DDR) were evaluated by WST-1, Annexin V, AO/PI, cell cycle and western blot analysis. Our results showed that the ELI and TAL combination could overcome TAL resistance by downregulating cell cycle checkpoint proteins and ATR-based DDR pathways through synergistic effects (ZIP score > 10). The overexpression of ATR and associated cell cycle proteins could play a role in PARPi resistance. However, this combination did not exert synergism in TNBC cells despite a higher apoptotic rate and increased DNA damage compared with the drug alone. Therefore, the dual targeting of ATR and PARP is a promising modality to reverse PARPi resistance with the downregulation of ATR-Chk1 based DNA damage response. However, further preclinical and clinical investigations should be required to elucidate the underlying molecular mechanisms behind ATRi and PARPi interactions in TNBC cells.

Gene editing technologies such as CRISPR/Cas9 have revolutionized functional genomics, yet their application in marine fish cell lines remains limited by inefficient delivery. This study compares three delivery strategies—electroporation, lipid nanoparticles (LNPs), and magnetofection using gelatin-coated superparamagnetic iron oxide nanoparticles (SPIONs)—for CRISPR/Cas9-mediated editing of the ifi27l2a gene in DLB-1 and SaB-1 cell lines. We evaluated transfection and editing efficiency, intracellular Cas9 localization, and genomic stability of the target locus. Electroporation achieved up to 95% editing in SaB-1 under optimized conditions, but only 30% in DLB-1, which exhibited locus-specific genomic rearrangements. Diversa LNPs enabled intracellular delivery and moderate editing (~25%) in DLB-1 but yielded only minimal editing in SaB-1, while SPION-based magnetofection resulted in efficient uptake but no detectable editing, highlighting post-entry barriers. Confocal imaging and fluorescence correlation spectroscopy suggested that nuclear localization and Cas9 aggregation may influence editing success, highlighting the importance of intracellular trafficking in CRISPR/Cas9 delivery. Our findings demonstrate that CRISPR/Cas9 delivery efficiency is cell line-dependent and governed by intracellular trafficking and genomic integrity. These insights provide a practical framework for optimizing gene editing in marine teleosts, advancing both basic research and selective breeding in aquaculture.

A starvation-triggered AAA+ ATPase halts chromosome replication progression by disassembling the bacterial DNA sliding clamp.

DNA repair mechanisms in human primary cells, including error-free repair, and, recurrent nuclease cleavage events, remain largely uncharacterised. We elucidate gene-editing related repair processes using Cleavage and Lesion Evaluation via Absolute Real-time dPCR (CLEAR-time dPCR), an ensemble of multiplexed dPCR assays that quantifies genome integrity at targeted sites. Utilising CLEAR-time dPCR we track active DSBs, small indels, large deletions, and other aberrations in absolute terms in clinically relevant edited cells, including HSPCs, iPSCs, and T-cells. By quantifying up to 90% of loci with unresolved DSBs, CLEAR-time dPCR reveals biases inherent to conventional mutation screening assays. Furthermore, we accurately quantify DNA repair precision, revealing prevalent scarless repair after blunt and staggered end DSBs and recurrent nucleases cleavage. This work provides one of the most precise analyses of DNA repair and mutation dynamics, paving the way for mechanistic studies to advance gene therapy, designer editors, and small molecule discovery.

Base excision repair (BER) is an important mechanism for maintaining genomic integrity and preventing DNA damage and mutations induced by oxidative stress. This study aimed to examine the relationship between oxidative stress and BER activity in newborn piglets by supplementing their mothers’ diets during pregnancy with long-chain n-3 polyunsaturated fatty acids (PUFAs) from algal and fish oils, provided either in natural form or as nanoparticles. BER enzyme activity was assessed using a nicking assay, and their gene expression levels by RT-qPCR in the livers of pregnant gilts and their offspring. Preliminary results indicated that maternal supplementation with oils rich in long-chain n-3 PUFAs significantly reduced (by 32%) BER capacity in the livers of their offspring. A corresponding decrease in mRNA expression of BER genes (TDG, MPG, OGG1) was observed in piglets from gilts receiving fish and algal oil supplements. Maternal supplementation with long-chain n-3 PUFAs may protect foetuses and neonates against oxidative stress, reducing DNA damage and enhancing genomic stability, which could positively influence early postnatal growth. The observed reduction in BER enzyme activity in newborn piglets likely reflected improved DNA integrity, and natural oil forms appeared more effective than their nanoparticle formulations. Disparities in socioeconomic areas related to access to functional foods with health-promoting properties highlight the importance of targeted strategies that integrate local systems and promote nutritional equity.

Nanoplastics: An emerging environmental concern in age-related diseases.

Senolytic therapy increases replicative capacity by eliminating senescent endothelial cells.

Deciphering deubiquitinating enzyme Ataxin-3 as an emerging target for cancer intervention.

Emerging role of SETD2 in the development and function of immune cells.

Circular RNAs (circRNAs) have emerged as promising candidates for neoantigen vaccine development due to their unique structural stability, enhanced translational efficiency, and immunostimulatory properties. Unlike linear RNAs, circRNAs exhibit exonuclease resistance, prolonged antigen expression, and increased activation of innate immune receptors such as RIG-I and MDA5, thereby enhancing anti-tumor immune responses. Preclinical studies have demonstrated that circRNA-based vaccines encoding tumor-specific neoantigens effectively stimulate Antigen- Presenting Cells (APCs), particularly Dendritic Cells (DCs), leading to robust CD8+ Cytotoxic T Lymphocyte (CTL) activation. This results in increased cytokine production, T-cell proliferation, and durable anti-tumor immunity. Compared to conventional neoantigen vaccine platforms, circRNA vaccines offer distinct advantages, including higher immunogenicity, improved cytosolic delivery, and minimal risk of genomic integration. CircRNA vaccines have demonstrated efficacy in preclinical tumor models, with studies highlighting their ability to induce long-term memory T-- cell responses and enhance the efficacy of immune checkpoint blockade therapies. However, challenges remain in optimizing circRNA delivery, mitigating unintended immune activation, and scaling up manufacturing processes. The translational potential of circRNA vaccines in tumor immunotherapy is significant, offering a novel and scalable approach to personalized cancer treatment. Further research and clinical validation are needed to optimize their design, improve manufacturing efficiency, and assess their efficacy in human trials. CircRNA vaccines represent a next-- generation platform with the potential to revolutionize cancer immunotherapy by harnessing durable and targeted anti-tumor immune responses.

WDFY2 promotes MRN complex formation required for homologous recombination-mediated DNA repair.