Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis最新文献

{"title":"Identification and validation of long noncoding RNA AC083900.1 and RP11-283C24.1 for prediction of progression of osteosarcoma","authors":"Liangkun Huang ,&nbsp;Wenyi Jin ,&nbsp;Yucheng Bao ,&nbsp;Xiaoshuang Zeng ,&nbsp;Yubiao Zhang ,&nbsp;Jianlin Zhou ,&nbsp;Hao Peng","doi":"10.1016/j.mrfmmm.2023.111828","DOIUrl":"10.1016/j.mrfmmm.2023.111828","url":null,"abstract":"<div><h3>Background</h3><p>The role of cuproptosis, an emerging cell death pathway that makes a remarkable contribution to tumor progression, remains elusive in osteosarcoma<span> (OS), in addition to its regulator, including long-no-coding RNAs (lncRNAs) that are also a critical factor for fueling OS.</span></p></div><div><h3>Methods</h3><p>Transcriptome and clinical data from 70 normal human bone tissue samples and 84 frozen clinical osteosarcoma samples were included in this study. Cuproptosis-associated lncRNAs (CRlncs) were identified through differential expression and co-expression analyses. Univariate Cox regression was performed to screen for prognostic lncRNAs, then we used least absolute shrinkage and selection operator regression to distinguish prognosis-related CRlncs (AC083900.1 and RP11-283C24.1) for modeling the CRlncs prognostic signature (CLPS) by multivariate Cox regression using the stepwise method. CLPS performance was tested by independent prognostic analyses, survival curve and receiver operating characteristic (ROC) curve. In addition, the molecular and immune mechanisms that underlie the unfavorable prognosis of CLPS-identified high-risk group were elucidated.</p></div><div><h3>Result</h3><p><span><span>AC083900.1 and RP11–283C24.1 have been identified as the most important CRlncs for OS progression (hazard ratio: 3.498 and 2.724, respectively), and the derived CLPS demonstrated outstanding performance for the prediction of OS prognosis (AUC of 0.799 and 0.778 in the training and test sets, both adj-p &lt; 0.05 in survival curve). As was anticipated, CLPS also outperformed a recent clinical prognostic approach that only achieved an AUC of 0.682 [metastasis]. It is notable that AC083900.1 progressed OS metastasis, evidenced by its high expression in metastatic OS, its high correlation to metastasis-related genes, and its high AUC of 0.683 for the prediction of metastasis. Mechanistically, AC083900.1 and RP11–283C24.1 dysregulated many critical biological processes regarding </span>humoral immune response, immunoglobulin complex, etc.; while reducing the </span>infiltration<span> of many cytotoxic immune cells<span> (B-cells, TIL, neutrophils, etc.). It is encouraging that BMS-509744 and KIN001–135 demonstrated high therapeutic implications for CLPS-identified high-risk OS, and the low-risk counterpart was sensitive to SB-216763. Quantitative RT-PCR analysis showed that both AC083900.1 and RP11-283C24.1 were significantly upregulated in different osteosarcoma cell lines.</span></span></p></div><div><h3>Conclusion</h3><p>This study elucidated the roles and mechanisms of AC083900.1 and RP11-283C24.1 in the development of OS, fostering a reliable prognostic approach and treatment for OS patients.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111828"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9776208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioinformatics analysis to identify breast cancer-related potential targets and candidate small molecule drugs","authors":"Huan Hong ,&nbsp;Haifeng Chen ,&nbsp;Junjie Zhao ,&nbsp;Long Qin ,&nbsp;Hongrui Li ,&nbsp;Haibo Huo ,&nbsp;Suqiang Shi","doi":"10.1016/j.mrfmmm.2023.111830","DOIUrl":"10.1016/j.mrfmmm.2023.111830","url":null,"abstract":"<div><h3>Objective</h3><p>The purpose of this study is to identify potential targets associated with breast cancer and screen potential small molecule drugs using bioinformatics analysis.</p></div><div><h3>Methods</h3><p><span><span>DEGs analysis of breast cancer tissues and normal breast tissues was performed using R language limma analysis on the GSE42568 and GSE205185 datasets. Functional enrichment analysis was conducted on the intersecting DEGs. The STRING analysis platform was used to construct a PPI network<span>, and the top 10 core nodes were identified using Cytoscape software. QuartataWeb was utilized to build a target-drug interaction network and identify potential drugs. Cell survival and proliferation were assessed using CCK8 and colony formation assays. </span></span>Cell cycle analysis<span> was performed using flow cytometry. Western blot analysis was conducted to assess protein levels of </span></span>PLK1, MELK, AURKA, and NEK2.</p></div><div><h3>Results</h3><p>A total of 54 genes were consistently upregulated in both datasets, which were functionally enriched in mitotic cell cycle and cell cycle-related pathways. The 226 downregulated genes were functionally enriched in pathways related to hormone level regulation and negative regulation of cell population proliferation. Ten key genes, namely <span><em>CDK1, CCNB2, ASPM, AURKA, </em><em>TPX2</em><span><span><span><em>, </em><em>TOP2A</em><em>, </em></span><em>BUB1B</em><em>, MELK, </em></span><em>RRM2</em><em>,</em></span></span> and <em>NEK2</em><span> were identified. The potential drug Fostamatinib was predicted to target AURKA, MELK, CDK1, and NEK2. </span><em>In vitro</em> experiments demonstrated that Fostamatinib inhibited the proliferation of breast cancer cells, induced cell arrest in the G2/M phase, and down-regulated MELK, AURKA, and NEK2 proteins.</p></div><div><h3>Conclusion</h3><p>In conclusion, Fostamatinib shows promise as a potential drug for the treatment of breast cancer by regulating the cell cycle and inhibiting the proliferation of breast cancer cells.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111830"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9776212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic treatment with ATR and CHK1 inhibitors does not substantially increase the mutational burden of human cells","authors":"Lisa Casimir ,&nbsp;Samuel Zimmer ,&nbsp;Félix Racine-Brassard ,&nbsp;Félix Goudreau ,&nbsp;Pierre-Étienne Jacques ,&nbsp;Alexandre Maréchal","doi":"10.1016/j.mrfmmm.2023.111834","DOIUrl":"10.1016/j.mrfmmm.2023.111834","url":null,"abstract":"<div><p><span><span><span>DNA replication stress (RS) entails the frequent slow down and arrest of replication forks by a variety of conditions that hinder accurate and processive genome duplication. Elevated RS leads to </span>genome instability, replication catastrophe and eventually cell death. RS is particularly prevalent in cancer cells and its exacerbation to unsustainable levels by chemotherapeutic agents remains a cornerstone of cancer treatments. The adverse consequences of RS are normally prevented by the ATR and CHK1 checkpoint kinases that stabilize stressed forks, suppress origin firing and promote </span>cell cycle arrest<span> when replication is perturbed. Specific inhibitors of these kinases have been developed and shown to potentiate RS and cell death in multiple in vitro cancer settings. Ongoing clinical trials are now probing their efficacy against various cancer types, either as single agents or in combination with mainstay chemotherapeutics. Despite their promise as valuable additions to the anti-cancer pharmacopoeia, we still lack a genome-wide view of the potential </span></span>mutagenicity<span><span> of these new drugs. To investigate this question, we performed chronic long-term treatments of TP53-depleted human cancer cells with ATR and CHK1 inhibitors (ATRi, AZD6738/ceralasertib and CHK1i, MK8776/SCH-900776). ATR or CHK1 inhibition did not significantly increase the mutational burden of cells, nor generate specific mutational signatures. Indeed, no notable changes in the numbers of base substitutions, short insertions/deletions and larger scale rearrangements were observed despite induction of replication-associated DNA breaks during treatments. Interestingly, ATR inhibition did induce a slight increase in closely-spaced mutations, a feature previously attributed to translesion </span>synthesis DNA<span> polymerases. The results suggest that ATRi and CHK1i do not have substantial mutagenic effects in vitro when used as standalone agents.</span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111834"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9927248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARP deficiency causes hypersensitivity to Taxol through oxidative stress induced DNA damage","authors":"Junko Maeda ,&nbsp;Ben Jepson ,&nbsp;Kohei Sadahiro ,&nbsp;Mami Murakami ,&nbsp;Hiroki Sakai ,&nbsp;Kazuki Heishima ,&nbsp;Yukihiro Akao ,&nbsp;Takamitsu A. Kato","doi":"10.1016/j.mrfmmm.2023.111826","DOIUrl":"10.1016/j.mrfmmm.2023.111826","url":null,"abstract":"<div><p><span>Taxol<span><span><span><span> is an antitumor drug<span> derived from the bark of the Pacific Yew tree that inhibits microtubule disassembly, resulting in cell cycle arrest<span> in late G2 and M phases. Additionally, Taxol increases cellular </span></span></span>oxidative stress<span> by generating reactive oxygen species. We hypothesized that the inhibition of specific DNA repair machinery/mechanisms would increase cellular sensitivity to the oxidative stress capacity of Taxol. Initial screening using </span></span>Chinese hamster<span><span> ovary (CHO) cell lines demonstrated that base excision repair deficiency, especially </span>PARP deficiency, caused cellular Taxol hypersensitivity. </span></span>Taxane diterpenes-containing </span></span><em>Taxus yunnanensis</em><span><span> extract also showed hypertoxicity in PARP deficient cells, which was consistent with other microtubule inhibitors like </span>colcemid<span><span><span>, vinblastine, and </span>vincristine. Acute exposure of 50 nM Taxol treatment induced both significant cytotoxicity and M-phase arrest in PARP deficient cells, but caused neither significant cytotoxicity nor late G2-M cell cycle arrest in wild type cells. Acute exposure of 50 nM Taxol treatment induced oxidative stress and DNA damage. The antioxidant </span>Ascorbic acid<span> 2 glucoside partially reduced the cytotoxicity of Taxol in PARP deficient cell lines. Finally, the PARP inhibitor Olaparib<span> increased cytotoxicity of Taxol in wild type CHO cells and two human cancer cell lines. Our study clearly demonstrates that cytotoxicity of Taxol would be enhanced by inhibiting PARP function as an enzyme implicated in DNA repair for oxidative stress.</span></span></span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111826"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9601349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-promoting roles of HMMR in lung adenocarcinoma","authors":"Qihao Wang ,&nbsp;Guomin Wu ,&nbsp;Linhai Fu ,&nbsp;Zhupeng Li ,&nbsp;Yuanlin Wu ,&nbsp;Ting Zhu ,&nbsp;Guangmao Yu","doi":"10.1016/j.mrfmmm.2022.111811","DOIUrl":"10.1016/j.mrfmmm.2022.111811","url":null,"abstract":"<div><p>Searching for differential genes in lung adenocarcinoma<span> (LUAD) is vital for research. Hyaluronan<span><span> mediated motility receptor (HMMR) promotes malignant progression of cancer patients. However, the molecular regulators of HMMR-mediated LUAD onset are unknown. This work aimed to study the relevance of HMMR to proliferation, migration and invasion of LUAD cells. Let-7c-5p and HMMR levels in LUAD cells and HLF-a cells were assessed, and their correlation was also detected. Their interaction was determined by dual-luciferase experiments and qRT-PCR. Cell proliferation, migration and invasion potentials in vitro were validated through cell counting kit-8 (CCK-8), colony formation, scratch healing, and transwell assays. The expression of HMMR was examined by qRT-PCR and </span>western blot and the expression of let-7c-5p was assayed by qRT-PCR. It was found that HMMR level was increased in LUAD and negatively correlated with let-7c-5p level. Let-7c-5p directly targeted HMMR to repress LUAD cell proliferation, migration and invasion. The above data illustrated that the let-7c-5p/HMMR axis may provide certain therapeutic value for LUAD patients.</span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"826 ","pages":"Article 111811"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9546450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between DNA repair capacity and body mass index in women","authors":"Ian Crespo-Orta ,&nbsp;Carmen Ortiz ,&nbsp;Jarline Encarnación ,&nbsp;Erick Suárez ,&nbsp;Jaime Matta","doi":"10.1016/j.mrfmmm.2022.111813","DOIUrl":"10.1016/j.mrfmmm.2022.111813","url":null,"abstract":"<div><h3>Objective</h3><p>Examine whether DNA repair capacity (DRC) levels are associated with body mass index (BMI) in adult women.</p></div><div><h3>Design and participants</h3><p>A nested study composed of 539 women without breast cancer (BC) from a case-control BC study in addition to 104 that were recruited later for a total of 643.</p></div><div><h3>Measurements</h3><p>DRC levels were measured in lymphocytes using a host-cell reactivation assay with a luciferase<span> reporter gene damaged by UVC. This assay measures the efficiency of nucleotide excision repair (NER). Log-binomial regression model was used. The prevalence ratio (PR) was used to evaluate the magnitude of the association between the BMI and DRC levels. An assessment of interaction terms was performed with the likelihood ratio test. The confounding effect was assessed by comparing the point estimates of the crude and adjusted PR.</span></p></div><div><h3>Results</h3><p>The 75th percentiles of DRC levels of the women with a BMI between 18 and 25 and &gt; 25 showed statistically significant differences. The prevalence of a DRC ≤ 5 % among women with BMI &gt; 25 is 1.24 (95 % CI: 1.03, 1.48) times the prevalence of having a DRC ≤ 5 % among the women with BMI ≤ 25 after adjustments for different covariates. This excess was statistically significant (<em>p</em> &lt; 0.05). Women with a family history of cancer had an estimated PR of 1.25 (95 % CI, 0.87–1.39; <em>P</em> ≥ 0.05); and women with no family history of cancer, the estimated PR was 1.6 (95 % CI, 1.14–2.22; <em>p</em> ≤ 0.05).</p></div><div><h3>Conclusions</h3><p>Women with BMI &gt; 25 tend to have lower DRC levels. When having a family history of cancer, the PR of low DRC levels in overweight/obese individuals was not statistically significant. However, the PR of low levels of DRC in overweight/obese individuals with no family history of cancer was statistically significant.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"826 ","pages":"Article 111813"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9871092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutagenesis induced by protonation of single-stranded DNA is linked to glycolytic sugar metabolism","authors":"Suzana P. Gelova ,&nbsp;Kin Chan","doi":"10.1016/j.mrfmmm.2023.111814","DOIUrl":"10.1016/j.mrfmmm.2023.111814","url":null,"abstract":"<div><p>Mutagenesis can be thought of as random, in the sense that the occurrence of each mutational event cannot be predicted with precision in space or time. However, when sufficiently large numbers of mutations are analyzed, recurrent patterns of base changes called mutational signatures can be identified. To date, some 60 single base substitution or SBS signatures have been derived from analysis of cancer genomics data. We recently reported that the ubiquitous signature SBS5 matches the pattern of single nucleotide polymorphisms (SNPs) in humans and has analogs in many species. Using a temperature-sensitive single-stranded DNA (ssDNA) mutation reporter system, we also showed that a similar mutational pattern in yeast is dependent on error-prone translesion DNA synthesis (TLS) and glycolytic sugar metabolism. Here, we further investigated mechanisms that are responsible for this form of mutagenesis in yeast. We first confirmed that excess sugar metabolism leads to increased mutation rate, which was detectable by fluctuation assay. Since glycolysis is known to produce excess protons, we then investigated the effects of experimental manipulations on pH and mutagenesis. We hypothesized that yeast metabolizing 8% glucose would produce more excess protons than cells metabolizing 2% glucose. Consistent with this, cells metabolizing 8% glucose had lower intracellular and extracellular pH values. Similarly, deletion of <em>vma3</em> (encoding a vacuolar H⁺-ATPase subunit) increased mutagenesis. We also found that treating cells with edelfosine (which renders membranes more permeable, including to protons) or culturing in low pH media increased mutagenesis. Analysis of the mutational pattern attributable to 20 µM edelfosine treatment revealed similarity to the SBS5-like TLS- and glycolysis-dependant mutational patterns previously observed in ssDNA. Altogether, our results agree with multiple biochemical studies showing that protonation of nitrogenous bases can alter base pairing so as to stabilize some mispairs, and shed new light on a common form of intrinsic mutagenesis.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"826 ","pages":"Article 111814"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9502397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient, robust, and versatile fluctuation data analysis using MLE MUtation Rate calculator (mlemur)","authors":"Krystian Łazowski","doi":"10.1016/j.mrfmmm.2023.111816","DOIUrl":"10.1016/j.mrfmmm.2023.111816","url":null,"abstract":"<div><p>The fluctuation assay remains an important tool for analyzing the levels of mutagenesis in microbial populations. The mutant counts originating from some average number of mutations are usually assumed to obey the Luria–Delbrück distribution. While several tools for estimating mutation rates are available, they sometimes lack accuracy or versatility under non-standard conditions. In this work, extensions to the Luria–Delbrück protocol to account for phenotypic lag and cellular death with either perfect or partial plating were developed. Hence, the novel MLE MUtation Rate calculator, or mlemur, is the first tool that provides a user-friendly graphical interface allowing the researchers to model their data with consideration for partial plating, differential growth of mutants and non-mutants, phenotypic lag, cellular death, variability of the final number of cells, post-exponential-phase mutations, and the size of the inoculum. Additionally, mlemur allows the users to incorporate most of these special conditions at the same time to obtain highly accurate estimates of mutation rates and <em>P</em> values, confidence intervals for an arbitrary function of data (such as fold), and perform power analysis and sample size determination for the likelihood ratio test. The accuracy of point and interval estimates produced by mlemur against historical and simulated fluctuation experiments are assessed. Both mlemur and the analyses in this work might be of great help when evaluating fluctuation experiments and increase the awareness of the limitations of the widely-used Lea–Coulson formulation of the Luria–Delbrück distribution in the more realistic biological contexts.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"826 ","pages":"Article 111816"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9506510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"XRCC8 mutation causes hypersensitivity to PARP inhibition without Homologous recombination repair deficiency","authors":"Junko Maeda ,&nbsp;Jeremy S. Haskins ,&nbsp;Takamitsu A. Kato","doi":"10.1016/j.mrfmmm.2023.111815","DOIUrl":"10.1016/j.mrfmmm.2023.111815","url":null,"abstract":"<div><p><span><span><span><span><span><span>PARP inhibitors inflict severe toxicity to </span>homologous recombination (HR) repair deficient cells because </span>DNA damages induced by PARP inhibition result in lethal DNA double strand breaks in the absence of HR repair during DNA replication. PARP inhibitors are the first clinically approved drugs designed for </span>synthetic lethality<span><span>. The synthetic lethal interaction of PARP inhibitors is not limited to HR repair deficient cells. We investigated radiosensitive mutants isolated from Chinese hamster lung origin V79 cells to identify novel synthetic lethal targets in the context of PARP inhibition. HR repair deficient </span>BRCA2 </span></span>mutant cells were used for positive control. Among tested cells, XRCC8 mutants presented hypersensitivity to PARP inhibitor, </span>Olaparib. XRCC8 mutants showed elevated sensitivity to </span>bleomycin<span> and camptothecin<span><span> similar to BRCA2 mutants. XRCC8 mutants presented an elevation of γ-H2AX foci formation frequency and S-phase dependent chromosome aberrations with Olaparib treatment. Enumerated damage foci following Olaparib treatment were observed to be elevated in XRCC8 as in BRCA2 mutants. Although this may suggest that XRCC8 plays a role in a similar DNA repair pathway as BRCA2 in HR repair, XRCC8 mutants presented functional HR repair including proper Rad51 foci formation and even elevated </span>sister chromatid exchange<span><span> frequencies with PARP inhibitor treatment. For comparison, RAD51 foci formation was suppressed in HR repair deficient BRCA2 mutants. Additionally, XRCC8 mutants did not display delayed mitotic entry with PARP inhibitors whereas BRCA2 mutants did. XRCC8 mutant cell line has previously been reported as possessing a mutation in the ATM gene. XRCC8 mutants displayed maximum cytotoxicity to ATM inhibitor among tested mutants and wild type cells. Furthermore, the ATM inhibitor sensitized XRCC8 mutant to ionzing radiation, however, XRCC8 mutant V-G8 expressed reduced levels of </span>ATM protein<span>. The gene responsible for XRCC8 phenotype may not be ATM but highly associated with ATM functions. These results suggest that XRCC8 mutation is a target for PARP inhibitor-induced synthetic lethality in HR repair independent manner via the disruption of cell cycle regulation. Our findings expand the potential application of PARP inhibitors in tumors lacking DNA damage responding genes other than HR repair, and further investigation of XRCC8 may contribute to this research.</span></span></span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"826 ","pages":"Article 111815"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9505471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of tafazzin and deoxyribonuclease 1 like 1 transcripts and X chromosome sequencing in the evaluation of the effect of mosaicism in the TAZ gene on phenotypes in a family affected by Barth syndrome","authors":"Teresa Płatek ,&nbsp;Maria Sordyl ,&nbsp;Anna Polus ,&nbsp;Agnieszka Olszanecka ,&nbsp;Sławomir Kroczka ,&nbsp;Bogdan Solnica","doi":"10.1016/j.mrfmmm.2022.111812","DOIUrl":"10.1016/j.mrfmmm.2022.111812","url":null,"abstract":"<div><p>Barth syndrome is a rare disease affecting mitochondria structure and function in males. In our previous study, we have shown a new mutation (c.83T&gt;A, p.Val28Glu) in the <em>TAZ</em> gene in two affected patients with congenital cardiomyopathy. Furthermore, women in this family had no mutations in their blood cells, whereas they only had mutations in the oral epithelial cells. The objective of the project was to evaluate the effect of intertissue mosaicisms on the Barth syndrome phenotypes, searching for another disease-related loci on chromosome X and finally to assess the consequences of the mutation. We conducted the advanced genetic study including cytogenetic research (constitutional karyotyping in blood and fibroblasts), NGS sequencing (with custom chromosome X sequencing together with the evaluation of loss of heterozygosity (LOH) and aberrations (CNV) in the whole genome) in four different tissues and sequencing of tafazzin and deoxyribonuclease 1 like 1 transcripts. The presence of deletions within the 5′untranslated region of the <em>TAZ</em> gene and/or the noncoding regions of the <em>DNASE1L1</em> gene were detected in several tissues. Whereas, there is no intertissue mosaicism regarding point mutation in <em>TAZ</em> gene in all investigated tissues in female carriers. Only the male patient presented biochemical markers and neurological symptoms of Barth syndrome. All the female carriers are healthy and have normal tafazzin and deoxyribonuclease 1 like 1 transcripts in 2 analyzed tissues. The conclusion of this study is that we cannot rule out or confirm mosaicism in the noncoding regions of <em>TAZ</em> or <em>DNASE1L1</em> genes, but this is not clinically relevant in female carriers because they are healthy. Finally, it has been proven that mutation (c.83T&gt;A, p.Val28Glu) is responsible for disease in males in this family.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"826 ","pages":"Article 111812"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9913415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}