Search Results (32)

DNA repair involves various intricate pathways that work together to maintain genome integrity. XPF (ERCC4) is a structural endonuclease that forms a heterodimer with ERCC1 that is critical in both single-strand break repair (SSBR) and double-strand break repair (DSBR). Although the mechanistic function of ERCC1/XPF has been established in nucleotide excision repair (NER), its role in long-patch base excision repair (BER) has recently been discovered through the 5′-Gap pathway. This study briefly explores the roles of XPF in different pathways to emphasize the importance of XPF in DNA repair. XPF deficiency manifests in various diseases, including cancer, neurodegeneration, and aging-related disorders; it is also associated with conditions such as Xeroderma pigmentosum and fertility issues. By examining the molecular mechanisms and pathological consequences linked to XPF dysfunction, this study aims to elucidate the crucial role of XPF in genomic stability as a repair protein in BER and provide perspectives regarding its potential as a therapeutic target in related diseases. Full article

Werner syndrome (WS) is an autosomal recessive disease caused by loss of function of WRN. WS is a segmental progeroid disease and shows early onset or increased frequency of many characteristics of normal aging. WRN possesses helicase, annealing, strand exchange, and exonuclease activities and acts on a variety of DNA substrates, even complex replication and recombination intermediates. Here, we review the genetics, biochemistry, and probably physiological functions of the WRN protein. Although its precise role is unclear, evidence suggests WRN plays a role in pathways that respond to replication stress and maintain genome stability particularly in telomeric regions. Full article

James German’s work to establish the natural history and cancer risk associated with Bloom syndrome (BS) has had a strong influence on the generation of scientists and clinicians working to understand other RECQ deficiencies and heritable cancer predisposition syndromes. I summarize work by us and others below, inspired by James German’s precedents with BS, to understand and compare BS with the other heritable RECQ deficiency syndromes with a focus on Werner syndrome (WS). What we know, unanswered questions and new opportunities are discussed, as are potential ways to treat or modify WS-associated disease mechanisms and pathways. Full article

Prostate cancer is the most common cancer and the second leading cause of cancer deaths among men in the USA. Several studies have demonstrated the antitumor properties of saffron in different types of cancers, including prostate cancer. The oral administration of saffron extract has been reported to have antitumor effects on aggressive prostate-cancer-cell-line-derived xenografts in nude male mice. The objective of this study was to carry out in vitro studies of saffron-treated prostate cancer cells to ascertain the effects of saffron on key intermediates in prostate carcinogenesis. Our studies demonstrated the significant inhibition of cell proliferation for androgen-sensitive prostate cancer cell lines via apoptotic pathways. We also demonstrate the statistically significant down-regulation of DNA methyltransferases (COMT, MGMT, EHMT2, and SIRT1 deacetylase) in saffron-treated prostate cancer cells. In addition, saffron-treated prostate cancer cells displayed a statistically significant dysregulation of DNA repair intermediates (WRN, p53, RECQ5, MST1R, and WDR70) in a time-dependent manner. Furthermore, Western blot analysis demonstrated that saffron treatment induced changes in the expression of other key genes (DNMT1, DNMT3b, MBD2, CD44, HDAC3, c-Myc, NF-kB, TNFα, AR, N-RAS, and PTEN) in prostate cancer cells. Collectively, our findings demonstrate the important mechanisms by which saffron mediates anti-tumor properties in prostate cancer. These findings suggest that the use of saffron supplements alongside standard treatment protocols may yield beneficial effects for individuals with prostate cancer. Full article

Arsenic is a carcinogenic metalloid toxicant widely found in the natural environment. Acute or prolonged exposure to arsenic causes a series of damages to the organs, mainly the liver, such as hepatomegaly, liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Therefore, it is imperative to seek drugs to prevent arsenic-induced liver injury. Quinazolines are a class of nitrogen heterocyclic compounds with biological and pharmacological effects in vivo and in vitro. This study was designed to investigate the ameliorating effects of quinazoline derivatives on arsenic-induced liver injury and its molecular mechanism. We investigated the mechanism of the quinazoline derivative KZL-047 in preventing and ameliorating arsenic-induced liver injury in vitro by cell cycle and apoptosis. We performed real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blotting combined with molecular docking. In vivo, the experiments were performed to investigate the mechanism of KZL-047 in preventing and ameliorating arsenic-induced liver injury using arsenic-infected mice. Physiological and biochemical indices of liver function in mouse serum were measured, histopathological changes in liver tissue were observed, and immunohistochemical staining was used to detect changes in the expression of RecQ-family helicases in mouse liver tissue. The results of in vitro experiments showed that sodium arsenite (SA) inhibited the proliferation of L-02 cells, induced apoptosis, blocked the cell cycle at the G1 phase, and decreased the expression of RecQ family helicase; after KZL-047 treatment in arsenic-induced L-02 cells, the expression of RecQ family helicase was upregulated, and the apoptosis rate was slowed, leading to the restoration of the cell viability level. KZL-047 inhibited arsenic-induced oxidative stress, alleviated oxidative damage and lipid peroxidation in vivo, and ameliorated arsenic toxicity-induced liver injury. KZL-047 restored the expression of RecQ family helicase proteins, which is consistent with the results of in vitro studies. In summary, KZL-047 can be considered a potential candidate for the treatment of arsenic-induced liver injury. Full article

Multiple studies have reported new or exacerbated persistent or resistant hypertension in patients previously infected with COVID-19. We used literature-based discovery to identify and prioritize multi-scalar explanatory biology that relates resistant hypertension to COVID-19. Cross-domain text mining of 33+ million PubMed articles within a comprehensive knowledge graph was performed using SemNet 2.0. Unsupervised rank aggregation determined which concepts were most relevant utilizing the normalized HeteSim score. A series of simulations identified concepts directly related to COVID-19 and resistant hypertension or connected via one of three renin–angiotensin–aldosterone system hub nodes (mineralocorticoid receptor, epithelial sodium channel, angiotensin I receptor). The top-ranking concepts relating COVID-19 to resistant hypertension included: cGMP-dependent protein kinase II, MAP3K1, haspin, ral guanine nucleotide exchange factor, N-(3-Oxododecanoyl)-L-homoserine lactone, aspartic endopeptidases, metabotropic glutamate receptors, choline-phosphate cytidylyltransferase, protein tyrosine phosphatase, tat genes, MAP3K10, uridine kinase, dicer enzyme, CMD1B, USP17L2, FLNA, exportin 5, somatotropin releasing hormone, beta-melanocyte stimulating hormone, pegylated leptin, beta-lipoprotein, corticotropin, growth hormone-releasing peptide 2, pro-opiomelanocortin, alpha-melanocyte stimulating hormone, prolactin, thyroid hormone, poly-beta-hydroxybutyrate depolymerase, CR 1392, BCR-ABL fusion gene, high density lipoprotein sphingomyelin, pregnancy-associated murine protein 1, recQ4 helicase, immunoglobulin heavy chain variable domain, aglycotransferrin, host cell factor C1, ATP6V0D1, imipramine demethylase, TRIM40, H3C2 gene, COL1A1+COL1A2 gene, QARS gene, VPS54, TPM2, MPST, EXOSC2, ribosomal protein S10, TAP-144, gonadotropins, human gonadotropin releasing hormone 1, beta-lipotropin, octreotide, salmon calcitonin, des-n-octanoyl ghrelin, liraglutide, gastrins. Concepts were mapped to six physiological themes: altered endocrine function, 23.1%; inflammation or cytokine storm, 21.3%; lipid metabolism and atherosclerosis, 17.6%; sympathetic input to blood pressure regulation, 16.7%; altered entry of COVID-19 virus, 14.8%; and unknown, 6.5%. Full article

Base excision repair (BER) corrects forms of oxidative, deamination, alkylation, and abasic single-base damage that appear to have minimal effects on the helix. Since its discovery in 1974, the field has grown in several facets: mechanisms, biology and physiology, understanding deficiencies and human disease, and using BER genes as potential inhibitory targets to develop therapeutics. Within its segregation of short nucleotide (SN-) and long patch (LP-), there are currently six known global mechanisms, with emerging work in transcription- and replication-associated BER. Knockouts (KOs) of BER genes in mouse models showed that single glycosylase knockout had minimal phenotypic impact, but the effects were clearly seen in double knockouts. However, KOs of downstream enzymes showed critical impact on the health and survival of mice. BER gene deficiency contributes to cancer, inflammation, aging, and neurodegenerative disorders. Medicinal targets are being developed for single or combinatorial therapies, but only PARP and APE1 have yet to reach the clinical stage. Full article

Strain Deinococcus irradiatisoli 17bor-2 was isolated from a soil sample exposed to γ radiation at Seoul Women’s University, Republic of Korea. The genus Deinococcus is a Gram-negative, coccus-shaped, and extremophilic bacterium, well renowned as being a radiation-resistant bacterium. Therefore, the mechanism behind the resistance to radiation and the gene responsible for the resistance could be helpful for detailed experimental studies with biotechnological applications. To study the involvement of genes in UV radiation resistance in strain 17bor-2, the genomic DNA of the strain was sequenced and constructed using the Pacific Biosciences RS II system. In addition, the complete genome sequence of strain 17bor-2 was annotated and interpreted using the Genomes–Expert Review (IMG-ER) system, along with Prodigal and JGI GenePRIMP analysis. The genome analysis of strain 17bor-2 revealed evidence of excinuclease UvrABC genes, which are key enzymes in the nucleotide excision repair (NER) mechanism, as well as genes from the recA-dependent and recQ pathways. The genome of strain Deinococcus irradiatisoli 17bor-2 was a circular chromosome comprising 3,052,043 bp with a GC content of 67.0%, including 2911 coding sequences (CDs), 49 tRNA genes, and 9 rRNA genes. In addition, their complete genome sequence annotation features provided evidence that radiation resistance genes play a central part in adaptation against extreme environmental conditions. In recent decades, excision repair genes have been indicated in considerable detail for both prokaryote and eukaryote resistance against UV-C radiation. Full article

Guanine-rich DNA can fold into highly stable four-stranded DNA structures called G-quadruplexes (G4). Originally identified in sequences from telomeres and oncogene promoters, they can alter DNA metabolism. Indeed, G4-forming sequences represent obstacles for the DNA polymerase, with important consequences for cell life as they may lead to genomic instability. To understand their role in bacterial genomic instability, different G-quadruplex-forming repeats were cloned into an Escherichia coli genetic system that reports frameshifts and complete or partial deletions of the repeat when the G-tract comprises either the leading or lagging template strand during replication. These repeats formed stable G-quadruplexes in single-stranded DNA but not naturally supercoiled double-stranded DNA. Nevertheless, transcription promoted G-quadruplex formation in the resulting R-loop for (G₃T)₄ and (G₃T)₈ repeats. Depending on genetic background and sequence propensity for structure formation, mutation rates varied by five orders of magnitude. Furthermore, while in vitro approaches have shown that bacterial helicases can resolve G4, it is still unclear whether G4 unwinding is important in vivo. Here, we show that a mutation in recG decreased mutation rates, while deficiencies in the structure-specific helicases DinG and RecQ increased mutation rates. These results suggest that G-quadruplex formation promotes genetic instability in bacteria and that helicases play an important role in controlling this process in vivo. Full article

Background: The genes of the RECQ DNA helicase family play a part in preserving the stability of the genome and controlling different disease mechanisms. However, the expression features of RECQs in relation to pan-cancer, their correlation with the immune microenvironment of tumors, and the landscape of prognostic power are still undisclosed. Methods: Various sequence and clinical data extracted from 33 cancers were utilized to generate a comprehensive overview of RECQs in the landscape. Afterward, we discovered variations in gene expression, potential enrichment of functions, genetic alterations, and analysis related to the immune response in tumors. Additionally, we explored the clinical characteristics and diagnostic significance of RECQs. And the important association of RECQL4 with liver hepatocellular carcinoma (LIHC) was investigated. Results: RECQs exhibited extensive mutations in different types of cancers. The expression of RECQ may be influenced by an oncogenic mutation in certain types of cancer, resulting in the observed genomic and epigenetic changes in diverse tumor formations. Furthermore, RECQs originating from tumors exhibited a significant association with the immune microenvironment of the tumor, indicating their potential as promising targets for therapy. Patient prognosis was significantly associated with the majority of genes in the RECQ family. In LIHC, RECQL4 eventually emerged as a separate prognostic determinant. Conclusions: To summarize, RECQs are essential for the regulation of the immune system in tumors, and RECQL4 serves as a prognostic indicator in LIHC. The results of our study offer fresh perspectives on RECQs from a bioinformatics perspective and emphasize the importance of RECQs in the diagnosis and treatment of cancer. Full article

RECQ5, a member of the conserved RECQ helicase family, is the sole human RECQ homolog that has not been linked to a hereditary developmental syndrome. Nonetheless, dysregulation of RECQ5 has emerged as a significant clinical concern, being linked to cancer predisposition, cardiovascular disease, and inflammation. In cells, RECQ5 assumes a crucial role in the regulation of DNA repair pathways, particularly in the repair of DNA double-strand breaks and inter-strand DNA crosslinks. Moreover, RECQ5 exhibits a capacity to modulate gene expression by interacting with transcription machineries and their co-regulatory proteins, thus safeguarding against transcription-induced DNA damage. This review aims to provide an overview of the multifaceted functions of RECQ5 and its implications in maintaining genomic stability. We will discuss the potential effects of clinical variants of RECQ5 on its cellular functions and their underlying mechanisms in the pathogenesis of cancer and cardiovascular disease. We will review the impact of RECQ5 variants in the field of pharmacogenomics, specifically their influence on drug responses, which may pave the way for novel therapeutic interventions targeting RECQ5 in human diseases. Full article

The Rothmund–Thomson syndrome (RTS) is a rare autosomal recessive disease associated with poikiloderma, telangiectasias, sun-sensitive rash, hair growth problems, juvenile cataracts and, for a subset of some RTS patients, a high risk of cancer, especially osteosarcoma. Most of the RTS cases are caused by biallelic mutations of the RECQL4 gene, coding for the RECQL4 DNA helicase that belongs to the RecQ family. Cellular and post-radiotherapy radiosensitivity was reported in RTS cells and patients since the 1980s. However, the molecular basis of this particular phenotype has not been documented to reliably link the biological and clinical responses to the ionizing radiation (IR) of cells from RTS patients. The aim of this study was therefore to document the specificities of the radiosensitivity associated with RTS by examining the radiation-induced nucleo-shuttling of ATM (RIANS) and the recognition and repair of the DNA double-strand breaks (DSB) in three skin fibroblasts cell lines derived from RTS patients and two derived from RTS patients’ parents. The results showed that the RTS fibroblasts tested were associated with moderate but significant radiosensitivity, a high yield of micronuclei, and impaired DSB recognition but normal DSB repair at 24 h likely caused by a delayed RIANS, supported by the sequestration of ATM by some RTS proteins overexpressed in the cytoplasm. To our knowledge, this report is the first radiobiological characterization of cells from RTS patients at both molecular and cellular scales. Full article

DNA helicase unwinding activity can be inhibited by small molecules and by covalently bound DNA lesions. Little is known about the relationships between the structural features of DNA lesions and their impact on unwinding rates and processivities. Employing E.coli RecQ helicase as a model system, and various conformationally defined DNA lesions, the unwinding rate constants k_obs = k_U + k_D, and processivities P = (k_U/(k_U + k_D) were determined (k_U, unwinding rate constant; k_D, helicase-DNA dissociation rate constant). The highest k_obs values were observed in the case of intercalated benzo[a]pyrene (BP)-derived adenine adducts, while k_obs values of guanine adducts with minor groove or base-displaced intercalated adduct conformations were ~10–20 times smaller. Full unwinding was observed in each case with the processivity P = 1.0 (100% unwinding). The k_obs values of the non-bulky lesions T(6−4)T, CPD cyclobutane thymine dimers, and a guanine oxidation product, spiroiminodihydantoin (Sp), are up to 20 times greater than some of the bulky adduct values; their unwinding efficiencies are strongly inhibited with processivities P = 0.11 (CPD), 0.062 (T(6−4)T), and 0.63 (Sp). These latter observations can be accounted for by correlated decreases in unwinding rate constants and enhancements in the helicase DNA complex dissociation rate constants. Full article

A rare and autosomal recessive premature aging disorder, Werner syndrome (WS) is characterized by the early onset of aging-associated diseases, including shortening stature, alopecia, bilateral cataracts, skin ulcers, diabetes, osteoporosis, arteriosclerosis, and chromosomal instability, as well as cancer predisposition. WRN, the gene responsible for WS, encodes DNA helicase with a 3′ to 5′ exonuclease activity, and numerous studies have revealed that WRN helicase is involved in the maintenance of chromosome stability through actions in DNA, e.g., DNA replication, repair, recombination, and epigenetic regulation via interaction with DNA repair factors, telomere-binding proteins, histone modification enzymes, and other DNA metabolic factors. However, although these efforts have elucidated the cellular functions of the helicase in cell lines, they have not been linked to the treatment of the disease. Life expectancy has improved for WS patients over the past three decades, and it is hoped that a fundamental treatment for the disease will be developed. Disease-specific induced pluripotent stem (iPS) cells have been established, and these are expected to be used in drug discovery and regenerative medicine for WS patients. In this article, we review trends in research to date and present some perspectives on WS research with regard to the application of pluripotent stem cells. Furthermore, the elucidation of disease mechanisms and drug discovery utilizing the vast amount of scientific data accumulated to date will be discussed. Full article

Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18–4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene. Full article