Uterine Corpus Endometrial Carcinoma (UCEC) is a significant health concern with a complex genetic landscape impacting disease susceptibility and progression. This study aimed to unravel the spectrum of DNA repair gene mutations in Pakistani UCEC patients through Next Generation Sequencing (NGS) and explore their potential functional consequences via downstream analyses. NGS analysis of genomic DNA from 30 UCEC patients was conducted to identify clinically significant pathogenic mutations in DNA repair genes. This analysis revealed mutations in 4 key DNA repair genes: BRCA1, BRCA2, APC, and CDH1. Kaplan-Meier (KM) analysis was employed to assess the prognostic value of these mutations on patient overall survival (OS) in UCEC. To delve into the functional impact of these mutations, we performed RT-qPCR, immunohistochemistry (IHC), and western blot analyses on the mutated UCEC samples compared to their non-mutated counterparts. These results unveiled the up-regulation in the expression of the mutated genes, suggesting a potential association between the identified mutations and enhanced gene activity. Additionally, targeted bisulfite sequencing analysis was utilized to evaluate DNA methylation patterns in the promoters of the mutated genes. Strikingly, hypomethylation in the promoters of BRCA1, BRCA2, APC, and CDH1 was observed in the mutated UCEC samples relative to the non-mutated, indicating the involvement of epigenetic mechanisms in the altered gene expression. In conclusion, this study offers insights into the genetic landscape of DNA repair gene mutations in Pakistani UCEC patients. The presence of pathogenic mutations in BRCA1, BRCA2, APC, and CDH1, coupled with their down-regulation and hypermethylation, suggests a convergence of genetic and epigenetic factors contributing to genomic instability in UCEC cells. These findings enhance our understanding of UCEC susceptibility and provide potential avenues for targeted therapeutic interventions in Pakistani UCEC patients.

DNA repair is a critical factor in tumor progression as it impacts tumor mutational burden, genome stability, PD-L1 expression, immunotherapy response, and tumor-infiltrating lymphocytes (TILs). In this study, we present a prognostic model for hepatocellular carcinoma (HCC) that utilizes genes related to the DNA damage response (DDR). Patients were stratified based on their risk score, and groups with lower risk scores demonstrated better survival rates compared to those with higher risk scores. The prognostic model\'s accuracy in predicting 1-, 3-, and 5-year survival rates for HCC patients was analyzed using receiver operator curve analysis (ROC). Results showed good accuracy in predicting survival rates. Additionally, we evaluated the prognostic model\'s potential as an independent factor for HCC prognosis, along with tumor stage. Furthermore, nomogram was employed to determine the overall survival year of patients with HCC based on this independent factor. Gene set enrichment analysis (GSEA) revealed that in the high-risk group, apoptosis, cell cycle, MAPK, mTOR, and WNT cascades were highly enriched. We used training and validation datasets to identify potential molecular subtypes of HCC based on the expression of DDR genes. The two subtypes differed in terms of checkpoint receptors for immunity and immune cell filtration capacity.Collectively, our study identified potential biomarkers of HCC prognosis, providing novel insights into the molecular mechanisms underlying HCC.

During spaceflight, multiple unique hazardous factors, particularly microgravity and space radiation, can induce different types of DNA damage, which pose a constant threat to genomic integrity and stability of living organisms. Although organisms have evolved different kinds of conserved DNA repair pathways to eliminate this DNA damage on Earth, the impact of space microgravity on the expressions of these DNA repair genes and their regulatory miRNAs has not been fully explored. In this study, we integrated all existing datasets, including both transcriptional and miRNA microarrays in wild-type (WT) Caenorhabditis elegans that were exposed to the treatments of spaceflight (SF), spaceflight control with a 1g centrifugal device (SC), and ground control (GC) in three space experiments with the periods of 4, 8 and 16.5 days. The results of principal component analysis showed the gene expression patterns for five major DNA repair pathways (i.e., non-homologous end joining (NHEJ), homologous recombination (HR), mismatch repair (MMR), nucleotide excision repair (NER), and base excision repair (BER)) were well separated and clustered between SF/GC and SC/GC treatments after three spaceflights. In the 16.5-days space experiment, we also selected the datasets of dys-1 mutant and ced-1 mutant of C. elegans, which respectively presented microgravity-insensitivity and radiosensitivity. Compared to the WT C. elegans flown in the 16.5-days spaceflight, the separation distances between SF and SC samples were significantly reduced in the dys-1 mutant, while greatly enhanced in the ced-1 mutant for five DNA repair pathways. By comparing the results of differential expression analysis in SF/GC versus SC/GC samples, we found the DNA repair genes annotated in the pathways of BER and NER were prominently down-regulated under microgravity during both the 4- and 8-days spaceflights. While, under microgravity, the genes annotated in MMR were dominatingly up-regulated during the 4-days spaceflight, and those annotated in HR were mainly up-regulated during the 8-days spaceflight. And, most of the DNA repair genes annotated in the pathways of BER, NER, MMR, and HR were up-regulated under microgravity during the 16.5-days spaceflight. Using miRNA-mRNA integrated analysis, we determined the regulatory networks of differentially expressed DNA repair genes and their regulatory miRNAs in WT C. elegans after three spaceflights. Compared to GC conditions, the differentially expressed miRNAs were analyzed under SF and SC treatments of three spaceflights, and some altered miRNAs that responded to SF and SC could regulate the expressions of corresponding DNA repair genes annotated in different DNA repair pathways. In summary, these findings indicate that microgravity can significantly alter the expression patterns of DNA repair genes and their regulatory miRNAs in space-flown C. elegans. The alterations of the expressions of DNA repair genes and the dominating DNA repair pathways under microgravity are possibly related to the spaceflight period. In addition, the key miRNAs are identified as the post-transcriptional regulators to regulate the expressions of various DNA repair genes under microgravity. These altered miRNAs that responded to microgravity can be implicated in regulating diverse DNA repair processes in space-flown C. elegans.

P53 suppresses tumorigenesis through multiple cellular functions/mechanisms, including genomic stability surveillance. Recently, it has also be reported for its role in cancer immune response modulation. Deficiency in DNA repair pathways lead to the accumulation of genomic alterations and tumor mutation burden and in consequence resulting in the activation of immune response. We investigated the interaction of p53 and DNA repair gene mutations and their impact on tumor mutation burden and immune response in human malignancies by mining cBioPortal data of a range of human cancers. We found that in the majority of human cancers, p53 mutations are equally distributed between DNA repair gene mutation positive and negative cases and in a number of human cancers, p53 and DNA repair gene mutations have a tendency of co-occurrence. Only in colorectal cancer, there is a tendency of \'mutual exclusivity\' of mutations in p53 and DNA repair genes. In most tumors, p53 and DNA repair gene mutations have synergistic/additive effect in increasing tumor mutation burden, but not in colorectal cancer where they are mutually exclusive. The impact of p53 and DNA repair gene mutations and their interaction on tumor microenvironment immune cells are complex and tumor type specific and not always correlated with tumor mutation burden. In colorectal cancers, these two types of mutations resulted in similar immune cell subpopulation changes and in tumors where the mutations have a tendency of co-occurrence, p53 showed dominant roles on immune response, although they can also counter-act each other for their effect on certain immune cell subtypes.

UNASSIGNED: To construct a prognostic signature composed of DNA repair genes to effectively predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC).
UNASSIGNED: After downloading the transcriptome and clinical data of HNSCC from the Cancer Genome Atlas (TCGA), 499 patients with HNSCC were equally divided into training and testing sets. In the training set, 13 DNA repair genes were screened using univariate proportional hazard (Cox) regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct a risk model, which was validated in the testing set.
UNASSIGNED: In the training and testing sets, there were significant differences in the clinical outcomes of patients in the high- and low-risk groups showed by Kaplan-Meier survival curves (P < 0.001). Univariate and multivariate Cox regression analyses showed that the risk score had independent prognostic predictive ability (P < 0.001). At the same time, the immune cell infiltration, immune score, immune-related gene expression, and tumor mutation burden (TMB) of patients with HNSCC were also different between the high- and low-risk groups (P < 0.05). Finally, we screened several chemotherapeutics for HNSCC, which showed significant differences in drug sensitivity between the high- and low-risk groups (P < 0.05).
UNASSIGNED: This study constructed a 13-DNA-repair-gene signature for the prognosis of HNSCC, which could accurately and independently predict the clinical outcome of the patient. We then revealed the immune landscape, TMB, and sensitivity to chemotherapy drugs in different risk groups, which might be used to guide clinical treatment decisions.

Rad51, a DNA-repair-related gene, has been reported to be involved in multiple cancers. However, its link with immune infiltration in liver cancer still unknown. Therefore, more research into the roles and activities of Rad51 in hepatocellular carcinoma (HCC) is required. The International Cancer Genome Consortium (ICGC) was used to identify the DNA repair gene Rad51, and has been proved to be overexpressed in HCC patients. We plotted the Kapan-Meier curve, demonstrating that patients with high expression of Rad51 have a poor prognosis. By analyzing the patient data, we discovered that high expression of Rad51 in HCC is linked to clinical stage, pathological T stage, grade, and age. Rad51 was found to be an independent prognostic factor for HCC patients using the multivariate cox model. Moreover, Rad51 expression was found to be associated with the infiltration of immune cells (B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells) and was intimately linked to the expression of immune cell markers in HCC. Through the analysis of differentially coexpressed genes (DCGs) of Rad51, GO and KEGG enrichment analyses suggested that the expression level of Rad51 might be relevant to neuroactive ligand-receptor interactions, the cell cycle, DNA replication, homologous recombination, oocyte meiosis, and the Fanconi anemia pathway. These findings indicated that Rad51 is a valuable biomarker for the prognosis of patients with liver cancer and that its expression has a significant correlation with immune infiltrations.Abbreviations: HCC: hepatocellular carcinoma; ICGC: International Cancer Genome Consortium TCGA: The Cancer Genome Atlas; TIMER: Tumor Immune Estimation Resource; CAF: Cancer-associated fibroblast; GEPIA: Gene Expression Profiling Interactive Analysis; GSEA: Gene set enrichment analysis; OS: overall survival; PFS: progression-free survival; RFS: relapse-free survival; DSS: disease-specific survival. Partial cor: partial correlation coefficient; HPA: Human Protein Atlas; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; CAF: Cancer-associated fibroblast; DCGs: differentially co-expressed genes.

Climate change is considered a major threat to society and nature. UV irradiation is the most important environmental genotoxic agent. Thus, how elevated UV irradiation may influence human health and ecosystems has generated wide concern in the scientific community, as well as with policy makers and the public in general. In this study, we investigated patterns and mechanisms of UV adaptation in natural ecosystems by studying a gene-specific variation in the potato late blight pathogen, Phytophthora infestans. We compared the sequence characteristics of radiation sensitive 23 (RAD23), a gene involved in the nucleotide excision repair (NER) pathway and UV tolerance, in P. infestans isolates sampled from various altitudes. We found that lower genetic variation in the RAD23 gene was caused by natural selection. The hypothesis that UV irradiation drives this selection was supported by strong correlations between the genomic characteristics and altitudinal origin (historic UV irradiation) of the RAD23 sequences with UV tolerance of the P. infestans isolates. These results indicate that the RAD23 gene plays an important role in the adaptation of P. infestans to UV stress. We also found that different climatic factors could work synergistically to determine the evolutionary adaptation of species, making the influence of climate change on ecological functions and resilience more difficult to predict. Future attention should aim at understanding the collective impact generated by simultaneous change in several climate factors on species adaptation and ecological sustainability, using state of the art technologies such as experimental evolution, genome-wide scanning, and proteomics.

Epidemiological studies have corroborated that respiratory diseases, including lung cancer, are related to fine particulate matter (<2.5 μm) (PM2.5) exposure. The toxic responses of PM2.5 are greatly influenced by the source of PM2.5. However, the effects of PM2.5 from Beijing on bronchial genotoxicity are scarce. In the present study, PM2.5 from Beijing was sampled and applied in vitro to investigate its genotoxicity and the mechanisms behind it. Human bronchial epithelial cells 16HBE were used as a model for exposure. Low (67.5 μg/mL), medium (116.9 μg/mL), and high (202.5 μg/mL) doses of PM2.5 were used for cell exposure. After PM2.5 exposure, cell viability, oxidative stress markers, DNA (deoxyribonucleic acid) strand breaks, 8-OH-dG levels, micronuclei formation, and DNA repair gene expression were measured. The results showed that PM2.5 significantly induced cytotoxicity in 16HBE. Moreover, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and cellular heme oxygenase (HO-1) were increased, and the level of glutathione (GSH) was decreased, which represented the occurrence of severe oxidative stress in 16HBE. The micronucleus rate was elevated, and DNA damage occurred as indicators of the comet assay, γ-H2AX and 8-OH-dG, were markedly enhanced by PM2.5, accompanied by the influence of 8-oxoguanine DNA glycosylase (OGG1), X-ray repair cross-complementing gene 1 (XRCC1), and poly (ADP-ribose) polymerase-1 (PARP1) expression. These results support the significant role of PM2.5 genotoxicity in 16HBE cells, which may occur through the combined effect on oxidative stress and the influence of DNA repair genes.

The aim of the present study was to investigate the radio-sensitizing efficacy of curcumin, a traditional Chinese medicine (TCM) on colon cancer cells in vitro and in vivo.
Human colon cancer HT-29 cells were treated with curcumin (2.5 μM), irradiation (10 Gy) and the combination of irradiation and curcumin. Cell proliferation was assessed using the MTT assay. Apoptotic cells were detected by Annexin V-PE/7-AAD analysis. PCR was performed to determine differential-expression profiling of 95 DNA-repair genes in irradiated cells and cells treated with both irradiation and curcumin. Differentially-expressed genes were confirmed by Western blotting. In vivo radio-sensitizing efficacy of curcumin was assessed in a xenograft mouse model of HT-29 colon cancer. Curcumin was administrated daily by intraperitoneal injection at 20 mg/kg/dose. Mice received irradiation (10 Gy) twice weekly. Apoptosis of the cancer cells following treatment was determined by TUNEL staining.
Irradiation induced proliferation inhibition and apoptosis of HT-29 cells in vitro. Concurrent curcumin treatment sensitized the HT-29 tumor to irradiation (p<0.01). DNA repair-related genes CCNH and XRCC5 were upregulated and LIG4 and PNKP downregulated by the combination of curcumin and irradiation compared with irradiation alone (p<0.05). Combined treatment of curcumin and irradiation resulted in a significantly greater tumor-growth inhibition and apoptosis compared to irradiation treatment alone (p<0.01).
Curcumin sensitizes human colon cancer in vitro and in vivo to radiation. Downregulation of LIG4 and PNKP and upregulation of XRCC5 and CCNH DNA-repair-related genes were involved in the radio-sensitizing efficacy of curcumin in colon cancer.

This network meta-analysis (NMA) was conducted to compare the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC). These included ERCC1 (rs11615, rs3212986, rs3212948), XRCC1 (rs25487, rs25489, rs1799782), XPD (rs13181, rs1799793), XPG (rs1047768, rs17655), XPA (rs1800975), XRCC3 (rs861539), APE1 (rs3136820), and RRM1 (rs1042858). The PubMed and Cochrane library databases were reviewed from their inception to February 2017 and studies which met our inclusion criteria were included in our investigation. This network meta-analysis combines direct and indirect evidence to assess the predictive value of 14 SNPs in eight DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC. We evaluated the predictive value through the use of the odd ratios (OR) and drawing surface under the cumulative ranking curves (SUCRA). A total of 26 eligible cohort studies were enrolled in this NMA. The pairwise meta-analysis indicated that in terms of overall response ratio (ORR), ERCC1 (rs11615), XRCC1 (rs25487, rs1799782), and XPD (rs13181) polymorphisms are associated with the efficacy of platinum-based chemotherapy in NSCLC. The result of this NMA suggests that there is no significant difference in predictive value of 8 DNA repair genes on the efficacy of platinum-based chemotherapy in NSCLC patients. The rank of SUCRA values of the 14 SNPs in the eight DNA repair genes were: XPD (rs1799793)→ERCC1 (rs3212986)→XPA(rs1800975)→ERCC1(rs3212948)→XRCC1(rs25487)→XRCC3(rs861539)→APE1(rs3136820)→ERCC1(rs11615)→XRCC1(rs1799782)→RRM1(rs1042858)→XPD(rs13181)→XPG (rs1047768)→XPG(rs17655)→XRCC1(rs25489). ERCC1(rs11615), XRCC1(rs25487, rs1799782) and XPD(rs13181) polymorphisms were better predictors in evaluating the efficacy of platinum-based chemotherapy in NSCLC patients. J. Cell. Biochem. 118: 4782-4791, 2017. © 2017 Wiley Periodicals, Inc.