Overexpression of the base excision repair NTHL1 glycosylase causes genomic instability and early cellular hallmarks of cancer

Limpose, Kristin; Trego, Kelly S.; Li, Zhentian; Leung, Sara W.; Sarker, Altaf H.; Shah, Jason A.; Ramalingam, Suresh S.; Werner, Erica; Dynan, William S.; Cooper, Priscilla K.; Corbett, Anita H.; Doetsch, Paul W.

doi:10.1093/nar/gky162

Cited by 36 publications

(28 citation statements)

References 54 publications

(90 reference statements)

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“…Another limitation is that we failed to detect the protein expression of NTH1 by utilizing western blot due to the weak signaling. Although NTH1 mRNA expression showed positive correlation with its protein expression [55], we plan to reexamine its protein expression. It needs to be noted that we dissolved lycopene in DMSO, whereas ATRA and BC were dissolved in ethanol.…”

Section: Discussionmentioning

confidence: 99%

Lycopene Protects against Smoking-Induced Lung Cancer by Inducing Base Excision Repair

et al. 2020

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Background: Oxidative stress plays a critical role in lung cancer progression. Carotenoids are efficient antioxidants. The objective of this study was to explore the efficacy of all-trans retinoic acid (ATRA) and carotenoids in cigarette smoke-induced oxidative stress within A549 human lung cancer epithelial cells. Methods: A549 cells were pretreated with 1-nM, 10-nM, 100-nM, 1-μM and 10-μM ATRA, β-carotene (BC) and lycopene for 24 h, followed by exposure to cigarette smoke using a smoking chamber. Results: The OxyBlot analysis showed that smoking significantly increased oxidative stress, which was inhibited by lycopene at 1 nM and 10 nM (p < 0.05). In the cells exposed to smoke, lycopene increased 8-oxoguanine DNA glycosylase (OGG1) expression at 1 nM, 10 nM, 100 nM, and 1 μM (p < 0.05), but not at 10 μM. Lycopene at lower doses also improved Nei like DNA glycosylases (NEIL1, NEIL2, NEIL3), and connexin-43 (Cx43) protein levels (p < 0.05). Interestingly, lycopene at lower concentrations promoted OGG1 expression within the cells exposed to smoke to an even greater extent than the cells not exposed to smoke (p < 0.01). This may be attributed to the increased SR-B1 mRNA levels with cigarette smoke exposure (p < 0.05). Conclusions: Lycopene treatment at a lower dosage could inhibit smoke-induced oxidative stress and promote genome stability. These novel findings will shed light on the molecular mechanism of lycopene action against lung cancer.

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Section: Discussionmentioning

confidence: 99%

Lycopene Protects against Smoking-Induced Lung Cancer by Inducing Base Excision Repair

et al. 2020

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“…One of the duplicated genes is NTHL1. Its overexpression causes genomic instability and loss of contact inhibition of cells [39]. Another duplicated gene in chr.16p13.3 is PRKD1.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of RAD9A intron 2 in childhood cancer patients, leukemia and tumor cell lines suggest a role for oncogenic transformation

Galetzka

Boeck

Dittrich

et al. 2020

Preprint

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Background: Most childhood cancers occur sporadically and cannot be explained by an inherited mutation or an unhealthy lifestyle. This suggests other predisposition defects that may support the oncogenic transformation of cells, e.g. via impaired DNA-repair. Our study consequently aims to investigate the impact of increased methylation of intron 2 of RAD9A in cancer patients which may be associated with oncogenic transformation. Methods: We performed an epimutation screen of RAD9A and other candidate genes ( APC , CDKN2A , EFNA5 , and TP53 ) using bisulfite pyrosequencing and deep bisulfite sequencing (DBS) in skin fibroblasts of 20 patients with primary cancer in childhood and second primary cancer (2N) later in life, 20 matched patients with only one primary cancer (1N) in childhood and 20 matched cancer-free (0N) controls. Furthermore, we analyzed leukemia cancer samples, tumor cell lines, EBV lymphoblasts and FaDu subclones. Radiation, colony formation assays, cell proliferation, PCR and molecular karyotype SNP-array experiments were performed. Data were analyzed using the Kruskal-Wallis rank-sum test, Benjamini-Hochberg procedure, REML and R-scripts. Results: Four 1N patients and one 2N patient displayed elevated mean methylation levels (>10%) in intron 2 of RAD9A . DBS of RAD9A in these patients revealed >2% hypermethylated alleles consistent with relevant epimutations. We found RAD9A hypermethylation in the bone marrow of patients with pre-ALL (pre-acute lymphoblastic leukemia), AML (acute myeloid leukemia), NHL (non-Hodgkin lymphoma), PBL (plasmablastic lymphoma) and EBV-(Epstein Barr virus) transformed lymphoblastoid cells. Molecular karyotyping of AML samples with hypermethylated RAD9A showed an evolving duplication of 1.8 kb on Chr16p13.3 including the PKD1 gene. In generated FaDu subclones with hypermethylated RAD9A, we found a homozygous inactivation of CHD2, SPATA8 , SMARCA1 and a 302 kb duplication including genes deregulated in cancer. The detected aberrations proved to influence cell viability. RAD9A methylation was not affected by radiation or the chemotherapeutical daunorubicin.Conclusion: The analysis of patient samples, cell lines and subclones suggest a connection between methylation levels of the RAD9A intron 2 locus and inactivation or amplification of important genes and survival of the cells. We propose that RAD9A epimutations may have an impact on leukemia, tumorigenesis, cancer progression and can potentially serve as a valuable biomarker.

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“…Emmanuel found that mismatch repair genes mutations in ovarian cancer can promote the growth of tumor cells to a distance and worsen the clinical physiology of patients [37]. Kristin discovered that the excision repair system was abnormally high in the early stage of many tumor cells and promotes tumor malignant progression [38]. Evan found that the process of tumor formation was diverse, but the cell cycle was a part that cannot be ignored [39].…”

Section: Discussionmentioning

confidence: 99%

TIMELESS is a Potential Molecular Marker in Glioma: A Study Based on Multiple Databases and Methods

Liu

Ren

Han

et al. 2020

Preprint

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Background: In recent years, some studies have shown that TIMELESS, as an oncogene, is involved in the malignant progression of cancers. However, its relationship with the prognosis of glioma patients is rarely reported. Our purpose is to explore the role of TIMELESS in glioma. Main body: Based on 1814 glioma samples from multiple databases such as TCGA, CGGA, GEO, we use a variety of bioinformatics methods to verify the mechanism of action of TIMELESS in glioma from mRNA to protein, from appearance to mechanism analysis, from clinical features to prognosis. Then, use the CMap tool to predict potential drugs that inhibit the expression of TIMELESS. First, we found TIMELESS is highly expressed in glioma from the mRNA level to the protein level. Second, TIMELESS is an independent risk factor for prognosis and has a suitable clinical diagnosis value in glioma. It was also positively correlated with WHO grade, age, histology, and negatively correlated with IDH1 mutation and 1p19q codeletion. Third, Base excision, cell cycle, and mismatch repair pathway were activated by TIMELESS in glioma. At last, we predict small molecules that potentially inhibit TIMELESS such as 8-azaguanine, gw8510, 6-thioguanosine, and ursodeoxycholic acid. Conclusion: This study is the first comprehensive analysis of TIMELESS, revealing the relationship between the novel oncogene and the clinical characteristics of patients with glioma, and the mechanism leading to poor prognosis. It also provides a potential biomarker for the diagnosis and treatment of glioma. Our research hopes to reveal the pathological progress of glioma at the genetic level.

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Overexpression of the base excision repair NTHL1 glycosylase causes genomic instability and early cellular hallmarks of cancer

Cited by 36 publications

References 54 publications

Lycopene Protects against Smoking-Induced Lung Cancer by Inducing Base Excision Repair

Lycopene Protects against Smoking-Induced Lung Cancer by Inducing Base Excision Repair

Hypermethylation of RAD9A intron 2 in childhood cancer patients, leukemia and tumor cell lines suggest a role for oncogenic transformation

TIMELESS is a Potential Molecular Marker in Glioma: A Study Based on Multiple Databases and Methods

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