Search Results (132)

Background: Oral squamous cell carcinoma (OSCC) remains a major public health challenge, particularly in South Asian populations where environmental exposures such as tobacco and areca nut consumption contribute significantly to disease burden. Although genomic studies have improved understanding of oral cancer biology, population-specific genomic data from high-risk Indian populations remain limited. This study aimed to characterize the genomic landscape of OSCC using whole-exome sequencing (WES) of fresh biopsy specimens obtained from patients residing along the southwest coast of Karnataka, India. Methods: Paired tumor and adjacent normal tissues from ten OSCC samples (total n = 20 samples) were subjected to WES to identify somatic and germline-associated variants. Matched tumor–normal comparative analysis, variant annotation, and population frequency assessment using established genomic databases, including gnomAD, were performed to characterize the mutational profile. The findings were further compared with a previously analyzed regional cohort comprising 66 OSCC patients to evaluate recurrence patterns and population relevance. Results: The analysis identified a broad background of recurrent germline-associated variants alongside a comparatively limited number of tumor-specific somatic mutations, consistent with the expected predominance of constitutional genetic variation relative to acquired coding alterations in tumor samples. Recurrent variants were observed in genes associated with DNA repair, immune signaling, inflammatory responses, and pharmacogenomic pathways, including XRCC1, ITPKB, ABCB1, and OPRM1, whereas somatic alterations were primarily detected in established cancer-associated genes such as TP53, CDKN2A, and TERT. Conclusions: Several recurrent variants demonstrated high frequencies in South Asian populations, suggesting that they may represent recurrent population-associated variants of potential biological or pharmacogenomic relevance that require validation in larger cohorts. KEGG pathway enrichment analysis identified pathways related to cancer, chemical carcinogenesis, metabolic regulation, and xenobiotic response. Overall, these findings provide preliminary insights into the population-specific genomic characteristics of OSCC in this regional cohort and highlight the need for larger validation studies to determine the biological significance and reproducibility of these findings. Full article

Lactylation is an emerging lactate-derived post-translational modification that may link tumour metabolic reprogramming, epigenetic regulation and DNA damage repair. Enhanced glycolysis and lactate accumulation are common in many tumours, and lactate has been reported to induce histone and non-histone lactylation in specific experimental contexts. Recent studies suggest that lactylation is associated with several DNA repair pathways, including base excision repair/single-strand break repair, nucleotide excision repair, homologous recombination and non-homologous end joining, and may contribute to therapy resistance in selected cancer models. Specifically, XRCC1 lactylation has been reported to promote nuclear translocation and repair activity in glioblastoma models; H4K12 lactylation has been linked to PARP inhibitor resistance through RAD23A activation in ovarian cancer models; and BLM lactylation has been associated with enhanced homologous recombination repair in bladder cancer models. Lactylation of NBS1, RAD51 and XLF has also been implicated in DNA repair regulation in specific experimental systems, although some mechanistic links are inferred from pathway activation or functional rescue experiments rather than directly demonstrated across multiple tumour types. These findings suggest that lactylation may modulate DNA repair and therapeutic response in a context-dependent manner. Targeting lactate metabolism, transport and lactylation regulators, including LDHA, MCT1/4, ACAT1, AARS1 and GCN5, or using site-specific lactylation-inhibiting peptides may improve chemotherapy and PARP inhibitor efficacy, but clinical translation remains limited by heterogeneity, metabolic plasticity, toxicity and insufficient validation. Full article

Background and Objectives: Migraine is a chronic, throbbing type of headache that affects large populations worldwide. This condition is associated with neuroinflammation. Materials and Methods: In this study, polymorphism analyses were performed by KASP PCR. Serum interleukin-6 (IL-6) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels were measured using kits based on the enzyme-linked immunosorbent assay (ELISA) principle. Results: In the APE1 Asp148Glu (rs1130409) gene polymorphism analysis, the frequency of the mutant G (Glu) allele was 93.1% and 48.0% in the control and migraine populations, respectively, while the frequency of the wild-type T (Asp) allele was 6.9% and 52.0% (p < 0.001). The frequency of the T/T (Asp/Asp) genotype was high in the migraine group (p < 0.001), while the frequency of the G/G (Glu/Glu) genotype was higher in the control group at 86.2%, compared to the migraine group (p < 0.001). The total frequency of the T/G+ G/G (Asp/Glu+Glu/Glu) composite genotype was determined to be 65.9% in the control group and 34.1% in the migraine group (p < 0.001). There was no statistical difference in allele and genotype frequency between the control and migraine groups for the XRCC1 Arg399Gln (rs25487) gene polymorphism. Serum 8-OHdG and IL-6 levels were comparable between the groups, with no statistically significant differences observed. Conclusions: Future studies with larger and more homogeneous populations are needed to further elucidate the potential interactions between inflammatory processes and DNA damage in migraine. Consideration of attack duration and environmental exposures may improve interpretation of biomarker variability. Expanding the analysis to additional DNA repair gene polymorphisms may also contribute to a better understanding of the molecular background of migraine and the evaluation of potential biomarkers. Full article

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders and has been linked to oxidative stress. Therefore, it can be hypothesized that NAFLD may be associated with genes encoding proteins involved in the base-excision repair (BER) pathway. Moreover, mitochondrial dysfunction plays a significant role in the development of NAFLD. In light of these observations, we suggested that fatty liver may be associated with genes that encode proteins responsible for mitochondrial DNA (mtDNA) degradation. This study evaluates single-nucleotide polymorphisms (SNPs) within the EXOG, ENDOG, POLG, FEN1, PARP1, and XRCC1 genes in 99 patients and 104 controls. SNP genotyping was performed using TaqMan probes and the findings were presented as odds ratios with corresponding 95% confidence intervals. Each of the eight investigated SNPs was found to modulate the risk of NAFLD occurrence. The analysis revealed that the studied haplotypes of EXOG and XRCC1 significantly affected the frequency of NAFLD in patients. The findings allow us to assume that there is a link between FEN1, PARP1, XRCC1, POLG, EXOG, and ENDOG and liver steatosis. We believe that the impaired repair and degradation of damaged mtDNA may have a significant impact on the development of NAFLD. Full article

Background: Breast cancer is the most prevalent malignant disease among women. Here, we investigate whether there is an association between disease recurrence in breast cancer patients and the quantitative methylation pattern of seven genes of different DNA repair pathways. Methods: Clinical and pathological data from 30 patients treated for sporadic breast cancer were selected according to the following inclusion criteria: follow-up of 5 years, adjuvant chemotherapy and recurrence. Histopathology was verified, and genomic DNA was accessed by tumor cryosectioning. We also determined the methylation levels of seven DNA repair genes (BRCA1, BRCA2, XRCC1, PARP1, ERCC4, MGMT, and XPC). Results: Patients without recurrence demonstrated a higher index of positive progesterone receptor status compared to patients with recurrence (p = 0.025). All other clinical characteristics of the patients did not differ between the groups. BRCA1 and BRCA2 genes showed methylation, and there was a higher level of BRCA1 gene methylation in patients without recurrence. BRCA1 methylation was not associated with the clinical characteristics of patients. All other genes analyzed showed no difference in methylation between patients with and without recurrence. Conclusions: We showed that sporadic breast cancer patients with a lower incidence of recurrence demonstrate a higher level of BRCA1 gene methylation after 5 years of follow-up, suggesting its role as a predictive biomarker. Full article

A growing body of epidemiological and toxicological evidence indicates that exposure to toxic elements (TEs), including As, Cd, Cr(VI), Pb, and Hg, is associated with a wide range of adverse health outcomes, including cancer, neurological and cardiovascular diseases. Given their widespread presence and toxicity, understanding the factors underlying inter-individual differences in susceptibility is essential, as not all exposed individuals develop the same health effects. Genetic variability, particularly single-nucleotide polymorphisms (SNPs), is increasingly recognized as a key determinant of individual responses to TE exposure. Variants in genes involved in metal transport, detoxification, and DNA repair, including DMT1, GSTP1, MT2A, hOGG1, and XRCC1, may influence internal dose and biological effects and have been proposed as potential susceptibility markers. However, current evidence remains inconsistent due to small sample sizes, heterogeneous exposure assessments, and limited considerations of ethnic diversity and gene–environment interactions. Future research should prioritize large and well-characterized populations integrating detailed exposure and lifestyle data. This review focuses on genetic susceptibility and gene–environment interactions in TE exposure, with particular emphasis on SNPs as key modulators of individual risk. It summarizes major toxic metals, reviews epidemiological evidence of the associated health risks, and highlights the role of genetic background in modulating TE-induced toxicity. Full article

We examined neocortical pathology and interneuron degeneration in neonatal hypoxia-ischemic encephalopathy (HIE). Piglets in two age groups (2–3 or 7–10 days old, n = 4–12/group) underwent global cerebral hypoxia–ischemia (HI) or sham treatment. Piglets (2–3 days old) had epidural electrodes for continuous electroencephalography (cEEG) and were treated with hypothermia (HT) or remained at normothermia (NT). Older piglets, all NT, had scalp EEG. Piglets at both ages had seizures and survived for 1–7 days. Cortical damage was assessed by hematoxylin & eosin staining and immunohistochemistry; calretinin (CR), parvalbumin (PV), and vasoactive intestinal peptide (VIP) interneurons (INs) were counted. Cell injury was assessed by DNA fragmentation and protein nitration. TAR DNA binding protein-43 (TDP43) and the DNA repair scaffold protein X-ray repair cross complementing-1 (XRCC1) were examined for degeneration mechanisms. Cortical layers 3 and 4 showed high vulnerability; damage emerged as isolated cells, focal and laminar, and distributed as panlaminar throughout different cortical regions that correlated with seizure burden. HT protected strongly against cortical damage. CR- and PV-INs were severely depleted in HI-NT piglets compared to sham. VIP INs appeared invulnerable. HT partially rescued the loss of INs. CR and PV formed nuclear and cytoplasmic inclusions that colocalized with TDP43 and XRCC1; co-immunoprecipitation identified interactions among these proteins, and tyrosine nitration of CR. CR and PV INs accumulated DNA single- and double-strand breaks and appeared as attritional apoptosis variants with proteinopathy. This cell death is identified as aggreosis. IN loss correlated with seizure presence. Postmortem human neonatal HIE cases had a similar loss of CR and PV INs and nuclear depletion of TDP43 in the neocortex. Thus, neonatal HIE causes the loss of neocortical inhibitory IN subtypes with vulnerabilities instructed by their intrinsic calcium-binding protein signature and by mechanisms consistent with toxic sequestration and the nuclear depletion of XRCC1 and TDP43 underlying DNA damage accumulation. Early inhibitory IN deletion could drive seizure evolution in HIE; TDP43 and XRCC1 could be therapeutic targets for neonatal HIE. Full article

Lead (Pb) and cadmium (Cd) are common environmental pollutants. Our previous population study revealed a significant positive association between Pb and Cd exposure and the micronuclei frequency among lead smelting workers. However, the underlying mechanisms remain unclear. In this study, human lymphoblastoid TK6 cells were used to investigate the genotoxicity and its mechanisms induced by individual or combined exposure to Pb and Cd. Our results showed that Pb and Cd exposure, alone or in combination, triggered oxidative stress, as evidenced by reduced antioxidant enzyme activity (GSH, SOD and CAT) and increased content of ROS and GSSG. Both metals induced pronounced DNA damage, as shown by elevated Tail DNA% in the Comet assay and γ-H2AX fluorescence intensity. Furthermore, Pb and/or Cd exposure caused inhibition of the DNA repair proteins, including BRCA1, CtIP, RAD52, and XRCC2, indicating impaired DNA repair capacity; and upregulated Bax expression and the Bax/Bcl-2 ratio and Caspase-3 with downregulation of Bcl-2. Notably, Pb and Cd co-exposure produced an antagonistic effect, modulating oxidative stress indicators, cell-cycle arrest, DNA damage markers, DNA repair and apoptosis-related proteins. These findings demonstrate that Pb and Cd induce oxidative stress, DNA damage, inhibition of DNA repair, and apoptosis in TK6 cells. Our study provides new insights into the mechanisms of heavy metal combined exposure–induced genotoxicity and identifies potential molecular targets for intervention. Full article

This study estimates the association between respiratory outcomes among employees of a secondary aluminum plant and airborne pollutants. Additionally, it looks into the relationship between pulmonary dysfunction in workers and X-Ray repair cross-complementing one (XRCC1) gene polymorphisms. 110 exposed workers and 58 non-exposed workers were enrolled in the study. Measurements were conducted on sulfur dioxide (SO₂), nitrogen dioxide (NO₂), and particulate particles. Pulmonary function was tested. Eosinophil cationic protein (ECP), C-reactive protein (CRP), matrix metalloproteinase-1 (MMP-1), interleukin 6 (IL6), granulocyte-macrophage colony-stimulating factor (GM-CSF), XRCC1 protein, and genotyping of XRCC1 gene polymorphisms were examined. The annual average concentrations of particulate matter (PM_2.5, PM₁₀), total suspended particulates (TSP), SO₂, and NO₂ were lower than the permissible limit. The areas around ovens, evaporators, and cold rolling mills exhibited the highest amounts. The majority of employees in these departments had impaired lung function. Prolonged exposure was associated with a significant decrease in forced expiratory volume in 1 s (FEV1%) and forced vital capacity (FVC%) among the exposed group (p = 0.001 & 0.04, respectively). Serum XRCC1 levels were significantly higher among exposed workers (p = 0.02). Inflammatory biomarkers showed no statistically significant differences between groups. Aluminum workers are at risk of developing respiratory disorders. The level of serum XRCC1 may serve as a potential biomarker for detecting susceptible workers. Full article

Hexavalent chromium [Cr(VI)] is a lung carcinogen. Central to its carcinogenic mechanism are Cr(VI)-induced DNA double strand breaks and chromosome instability. While breaks are usually repaired in healthy cells, Cr(VI) inhibits homologous recombination repair by targeting RAD51. RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) are responsible for RAD51 loading and the stabilization of nucleoprotein filaments necessary for DNA strand exchange and repair. This study aimed to investigate the effects of Cr(VI) exposure on RAD51 paralogs. WTHBF-6 cells, a human lung cell line, were exposed to various environmentally and occupationally relevant concentrations of zinc chromate for acute (24 h) and prolonged (120 h) exposure times. After exposure to Cr(VI), we collected RNA for sequencing and assessed the ability of DNA repair proteins to form foci using immunofluorescence. Protein levels were measured with western blotting, RNA-Seq was validated with RT-qPCR, and protein–protein interactions were assessed with the Proximity Ligation Assay (PLA) assay. Cr(VI) transcriptionally repressed all RAD51 paralogs. Further functional analyses showed that Cr(VI) inhibited the foci formation of RAD51D after acute and prolonged exposures and of XRCC2 and XRCC3 after prolonged exposure. Cr(VI) also inhibited overall RAD51D protein expression, as well as its interaction with RAD51. These findings suggest that Cr(VI) inhibits all RAD51 paralogs, but RAD51D might be an early target of Cr(VI), leading to the loss of RAD51 filament formation and function and the overall inhibition of homologous recombination repair. Full article

Hypoxia-inducible factor (HIF) is recognized as a key transcription factor via regulating a variety of molecular responses to hypoxia, although the details are still unclear. In this study, based on bioinformatics analysis, the expression of the HIF-1α gene in T. castaneum (TcHIF-1α) under hypoxic treatments was determined. After TcHIF-1α knockdown by injecting dsRNA, larval mortality, the expression levels of oxidative stress-related genes, and enzymatic activities were measured; DNA damage was also evaluated through single cell gel electrophoresis. The result indicated that TcHIF-1α is highly conserved in structure. TcHIF-1α exhibited distinct temporal patterns, with a peak after 72 h of exposure to 2% O₂. Following TcHIF-1α knockdown, a significant increase in larval mortality (17.44 ± 5.91%) and moderate DNA damage level was found. This might be accompanied by ROS accumulation, lipid peroxidation (LPO), and suppression of antioxidant enzymatic activities. The expression of genes involved in ROS synthesis (e.g., NOX) was significantly upregulated, whereas genes responsible for mitigating oxidative stress (e.g., OGG1, XRCC1, PARP1, SOD1a) were markedly downregulated. These findings elucidate the critical role of HIF-1α in insect hypoxia adaptation by regulating the antioxidative stress, highlighting its potential as a promising target for developing novel pest control strategies. Full article

DNA polymerase beta (Polβ) is a 39 kDa, single polypeptide enzyme that possesses both gap tailoring and nucleotidyl transferase activity and is the key polymerase involved in base excision repair (BER) and the final steps of active gene demethylation. We demonstrated that residues in the mouse Polβ protein, L301 and V303, are critical for Polβ’s interaction with the BER scaffolding protein X-ray repair cross-complementing 1 (XRCC1), and mutation of these residues impairs Polβ’s ability to bind to XRCC1, negatively impacting BER complex assembly. We developed Polβ^{L301R-V303R/L301R-V303R} knock-in mice to explore how defects with this essential protein complex impact genome stability in the mouse. We found these mice to be viable and fertile yet exhibited a modest reduction in body weight. Here, we examined the protein and mRNA levels in tissues from wild-type (WT), heterozygous (HET), and homozygous (HOM) Polβ^{L301R-V303R/L301R-V303R} mice and the derived fibroblast cell lines. We show that HOM mice have significantly diminished Polβ protein levels, as compared to WT mice, in several tissues, yet Polβ mRNA levels were not significantly different, suggesting the decreased levels of Polβ protein could not be attributed to lower gene expression. Upon examination of Polβ stability in mouse ear fibroblasts derived from WT and HOM mice, results are consistent with human cell studies that the Polβ^L301R-V303R protein is unstable and undergoes proteasome-mediated degradation. Finally, we evaluated WT, and HOM, liver and brain genomic DNA samples for 5-methylcytosine/5-hydroxymethylcytosine (5mC/5hmC) levels by nanopore sequencing to investigate the impact of suppressed Polβ protein levels on active gene demethylation. As expected, we found tissue-specific trends in methylation, when comparing the brain and liver. However, we were unable to discern substantial differences in methylation levels between WT and HOM mice, suggesting that in the absence of external stressors, low Polβ levels do not impact methylation patterns. Full article

The effect of sinusoidal Extremely Low-Frequency Electromagnetic Fields (ELF-EMFs) on gynecological (HeLa, ES-2) and urological (DU-145) cancer cells was investigated. ELF-EMFs with a frequency of 50 Hz and a magnetic flux density of 1.3 mT were applied for 15 and 30 min. The experiment was conceptualized to investigate the in vitro short-term effects of ELF-EMFs on cell reactive oxygen species (ROS) formation, the levels of genes and proteins involved in DNA damage response, and epigenetic modifications. Here, we found that ELF-EMFs treatment leads to an elevation in the ROS levels that contribute to distinct scenarios in the studied cancer cells. The most prominent changes in the studied factors were found in ES-2 and DU-145 cells exposed to 30 min of ELF-EMFs. ES-2 cells exhibited upregulation of XRCC5 gene expression and elevated levels of several proteins: TNF-α, RAD51, APE1, XRCC1, and NSUN2. Diminished levels of BCL-2, HSP90, RAD51, and TNF-α, as well as overexpression of VIM and METTL3, were observed in DU-145 cells. In summary, we postulate that short-term exposure to 50 Hz ELF-EMFs may be a promising treatment strategy for gynecological and urological cancer cells. Full article

Non-homologous end joining (NHEJ) is a critical DNA double-strand break (DSB) repair pathway that operates throughout the cell cycle to maintain the genomic stability of the cell. Unlike homologous recombination (HR), NHEJ is capable of repairing DSBs without the need for a homologous template, making it a rapid response mechanism, but potentially prone to errors. Central to NHEJ function and essential for the ligation through the recruitment and activation of additional repair factors, such as Artemis, XRCC4, and DNA ligase IV, is the DNA-dependent protein kinase (DNA-PK) complex. Dysregulation in the NHEJ pathway contributes to genomic instability, oncogenesis, and resistance to genotoxic therapies. Consequently, inhibitors of DNA-PK have emerged as promising therapeutic agents to sensitize tumor cells to radiation and DNA-damaging chemotherapeutics. Inhibiting the DNA-PK ability to recruit the protein complex needed for successful DSB repair promotes cell death through apoptosis or mitotic catastrophe. While inhibitors of DNA-PK can be used to enhance the effects of genotoxic therapies, the field still struggles to address critical problems: how to best exploit the differential DNA repair capacities among tumor subtypes, how to maximize radiosensitization of cancerous cells while sparing normal tissues, and how to translate preclinical studies into clinical benefits. Given that NHEJ constitutes the primary line of defense against radiation-induced damage, rapidly repairing the majority of double-strand breaks throughout the cell cycle, this review concentrates on targeting the DNA-PK complex, as the master regulator of this rapid-response mechanism, highlighting why its inhibition represents a strategic action to overcome intrinsic radioresistance. The implementation of DNA-PK inhibitors into medical practice can enable the stratification of oncologic patients into two categories, based on the tumors’ vulnerability to NHEJ disruptions. Thus, the therapeutic pathways of patients with NHEJ tumors could branch, combining traditional genotoxic therapies (radiation and DNA-damaging chemotherapeutics) with DNA-PK inhibitors to achieve an enhanced effect and improved survival outcomes. Full article

Background: Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, but only 15–30% of patients achieve a pathological complete response. Single nucleotide polymorphisms represent stable genetic markers with potential predictive value for treatment response. This systematic review synthesizes current evidence on the association between SNPs and the response to nCRT in rectal cancer. Methods: PubMed and Web of Science databases were searched for relevant English studies. Two reviewers independently screened the titles and abstracts using the DistillerSR tool. Full-text articles were assessed for their eligibility. Data extraction followed the PRISMA guidelines, and the risk of bias was assessed. Results: Thirty-two studies (4116 patients) assessed 304 SNPs across 126 genes in 407 analyses. DNA repair genes (XRCC1, XRCC3, ERCC1, ERCC2) and folate metabolism genes (MTHFR, TYMS) were most frequently investigated. Only two SNPs demonstrated predictive value in multiple studies: rs25487 (XRCC1) and rs1801133 (MTHFR); however, the associations were inconsistent. The remaining SNPs showed isolated associations in single studies. No SNP demonstrated predictive value across independent cohorts. Conclusions: Current evidence does not support the clinical use of individual SNPs to predict nCRT response in rectal cancer patients. Although XRCC1 and MTHFR polymorphisms have been extensively studied, their predictive utility remains inconclusive. Future research should prioritize large, multicenter prospective studies with standardized treatment and outcome definitions, and consider polygenic risk models or integrated multi-omic approaches. Full article