Rare coding variants in DNA damage repair genes associate with timing of natural menopause

Background– Defect in DNA damage repair genes due to oxidative stress predispose the humans to malignancies. There are many cases of association of malignancies with sickle cell disease patients (SCD) throughout the world, the molecular cause of which has never been investigated. DNA damage repair genes such as hOGG1, XRCC1 and p53 play significant role in repair of DNA damage during oxidative stress but the distribution and clinical effect of these genes are not known till date in SCD patients who are associated with oxidative stress related clinical complications. Objective – The aim of the study was to characterize the distribution and clinical effect of DNA damage gene polymorphisms p53 (codon 72 Arg> Pro), hOGG1 (codon 326 Ser>Cyst) and XRCC1 (codons 194 Arg>Trp, codon 280 Arg> His, codon 399 Arg> Gln) among SCD patients of central India. Methods- A case control study of 250 SCD patients and 250 normal individuals were investigated by PCR-RFLP techniques. Result- The prevalence of mutant alleles of hOGG1 gene, XRCC1 codon 280 Arg>His were found to be significantly high among SCD patients as compared to controls. However, SCD patients did not show clinical association with any of these DNA repair gene polymorphisms. Conclusion- This indicates that hOGG1, p53 and XRCC1 gene polymorphisms may not have any clinical impact among SCD patients in India.

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Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20194728 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4728 ◽

Cited By ~ 2

Author(s):

Hwani Ryu ◽

Hyun-Kyung Choi ◽

Hyo Jeong Kim ◽

Ah-Young Kim ◽

Jie-Young Song ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Tyrosine Kinase ◽

Small Molecule ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Class Iii ◽

Damage Repair ◽

Repair Genes

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

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Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504019x15555794826018 ◽

2020 ◽

Vol 28 (1) ◽

pp. 33-40 ◽

Cited By ~ 3

Author(s):

Annemarie E. M. Post ◽

Johan Bussink ◽

Fred C. G. J. Sweep ◽

Paul N. Span

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Dna Damage ◽

Dna Damage Repair ◽

Cross Resistance ◽

Damage Repair ◽

Breast Cancer Cohort ◽

Tamoxifen Resistant ◽

Repair Genes

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

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Altered expression of DNA damage repair genes in the brain tissue of mice conceived by in vitro fertilization

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa010 ◽

2020 ◽

Vol 26 (3) ◽

pp. 141-153

Author(s):

Minhao Hu ◽

Yiyun Lou ◽

Shuyuan Liu ◽

Yuchan Mao ◽

Fang Le ◽

...

Keyword(s):

Dna Methylation ◽

Dna Damage ◽

Brain Tissue ◽

Dna Damage Repair ◽

Damage Repair ◽

Gene And Protein Expression ◽

The Brain ◽

Repair Genes

Abstract Our previous study revealed a higher incidence of gene dynamic mutation in newborns conceived by IVF, highlighting that IVF may be disruptive to the DNA stability of IVF offspring. However, the underlying mechanisms remain unclear. The DNA damage repair system plays an essential role in gene dynamic mutation and neurodegenerative disease. To evaluate the long-term impact of IVF on DNA damage repair genes, we established an IVF mouse model and analyzed gene and protein expression levels of MSH2, MSH3, MSH6, MLH1, PMS2, OGG1, APEX1, XPA and RPA1 and also the amount of H2AX phosphorylation of serine 139 which is highly suggestive of DNA double-strand break (γH2AX expression level) in the brain tissue of IVF conceived mice and their DNA methylation status using quantitative real-time PCR, western blotting and pyrosequencing. Furthermore, we assessed the capacity of two specific non-physiological factors in IVF procedures during preimplantation development. The results demonstrated that the expression and methylation levels of some DNA damage repair genes in the brain tissue of IVF mice were significantly changed at 3 weeks, 10 weeks and 1.5 years of age, when compared with the in vivo control group. In support of mouse model findings, oxygen concentration of in vitro culture environment was shown to have the capacity to modulate gene expression and DNA methylation levels of some DNA damage repair genes. In summary, our study indicated that IVF could bring about long-term alterations of gene and protein expression and DNA methylation levels of some DNA damage repair genes in the brain tissue and these alterations might be resulted from the different oxygen concentration of culture environment, providing valuable perspectives to improve the safety and efficiency of IVF at early embryonic stage and also throughout different life stages.

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Stimulation of RAC1/PAK1 signalling upregulates DNA damage repair genes via the BCL6/STAT5-switch

Annals of Oncology ◽

10.1093/annonc/mdx361.069 ◽

2017 ◽

Vol 28 ◽

pp. v19-v20

Author(s):

P. Barros ◽

A.J. Amaral ◽

L.B. Abrantes ◽

T. Oliveira ◽

H. Louro ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Repair ◽

Damage Repair ◽

Repair Genes ◽

Stimulation Of

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Differences in Expression of Key DNA Damage Repair Genes after Epigenetic-Induced BRCAness Dictate Synthetic Lethality with PARP1 Inhibition

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-15-0374 ◽

2015 ◽

Vol 14 (10) ◽

pp. 2321-2331 ◽

Cited By ~ 20

Author(s):

Adrian P. Wiegmans ◽

Pei-Yi Yap ◽

Ambber Ward ◽

Yi Chieh Lim ◽

Kum Kum Khanna

Keyword(s):

Dna Damage ◽

Synthetic Lethality ◽

Dna Damage Repair ◽

Damage Repair ◽

Repair Genes

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Identification of Candidate Polymorphisms on Stress Oxidative and DNA Damage Repair Genes Related with Clinical Outcome in Breast Cancer Patients

International Journal of Molecular Sciences ◽

10.3390/ijms131216500 ◽

2012 ◽

Vol 13 (12) ◽

pp. 16500-16513 ◽

Cited By ~ 2

Author(s):

Patricia Rodrigues ◽

Jessica Furriol ◽

Begoña Bermejo ◽

Felipe Chaves ◽

Ana Lluch ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Clinical Outcome ◽

Cancer Patients ◽

Dna Damage Repair ◽

Breast Cancer Patients ◽

Damage Repair ◽

Stress Oxidative ◽

Repair Genes

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A Prognostic DNA Damage Repair Genes Signature and Its Impact on Immune Cell Infiltration in Glioma

Frontiers in Oncology ◽

10.3389/fonc.2021.682932 ◽

2021 ◽

Vol 11 ◽

Author(s):

Guohui Wang ◽

Huandi Zhou ◽

Lei Tian ◽

Tianfang Yan ◽

Xuetao Han ◽

...

Keyword(s):

Dna Damage ◽

High Risk ◽

Cox Regression ◽

Dna Damage Repair ◽

Risk Groups ◽

Immune Microenvironment ◽

Damage Repair ◽

Immunosuppressive Cells ◽

Repair Genes ◽

Genome Atlas

ObjectiveGlioma is the most frequent type of malignant cerebral tumors. DNA damage repair genes (DDRGs) play a crucial role in the development of cancer. In this study, we constructed a DDRGs signature and investigated the potential mechanisms involved in this disease.MethodsRNA sequence data, microarray data, and corresponding clinical information of gliomas were downloaded from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO). Subsequently, we identified candidate genes by differential analysis and Cox regression analysis. The least absolute shrinkage and selection operator Cox regression model was utilized to construct a DDRGs signature using TCGA training dataset. According to this signature, patients with glioma were divided into low- and high-risk groups. The predictive ability of the signature was validated by prognostic analysis, receiver operating characteristic curves, principal component analysis, and stratification analysis in TCGA testing and CGGA verification datasets. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate the immune microenvironment of glioma. Moreover, we conducted GSEA to determine the functions and pathways in the low- and high-risk groups. Finally, a nomogram was constructed by combining the signature and other clinical features.ResultsA total of 1,431 samples of glioma (592 from TCGA, 686 from the CGGA, and 153 from the GEO) and 23 samples of normal brain tissue from the GEO were analyzed in this study. There were 51 prognostic differentially expressed DDRGs. Additionally, five DDRGs (CDK4、HMGB2、WEE1、SMC3 and GADD45G) were selected to construct a DDRGs signature for glioma, stratifying patients into low- and high-risk groups. The survival analysis showed that the DDRGs signature could differentiate the outcome of the low- and high-risk groups, showing that high-risk gliomas were associated with shorter overall survival. The immune microenvironment analysis revealed that more immunosuppressive cells, such as tumor associated macrophages and regulatory T cells, were recruited in the high-risk group. GSEA also showed that high-risk glioma was correlated with the immune and extracellular matrix pathways.ConclusionThe five DDRGs signature and its impact on the infiltration of immunosuppressive cells could precisely predict the prognosis and provide guidance on the treatment of glioma.

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