scholarly journals DNA repair- and nucleotide metabolism-related genes exhibit differential CHG methylation patterns in natural and synthetic polyploids (Brassica napus L.)

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Liqin Yin ◽  
Zhendong Zhu ◽  
Liangjun Huang ◽  
Xuan Luo ◽  
Yun Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Brassica Napus ◽  
Genomic Instability ◽  
Dna Damage Repair ◽  
Nucleotide Metabolism ◽  
Repair System ◽  
Damage Repair ◽  
Methylation Patterns ◽  
Natural And Synthetic

AbstractPolyploidization plays a crucial role in the evolution of angiosperm species. Almost all newly formed polyploids encounter genetic or epigenetic instabilities. However, the molecular mechanisms contributing to genomic instability in synthetic polyploids have not been clearly elucidated. Here, we performed a comprehensive transcriptomic and methylomic analysis of natural and synthetic polyploid rapeseeds (Brassica napus). Our results showed that the CHG methylation levels of synthetic rapeseed in different genomic contexts (genes, transposon regions, and repeat regions) were significantly lower than those of natural rapeseed. The total number and length of CHG-DMRs between natural and synthetic polyploids were much greater than those of CG-DMRs and CHH-DMRs, and the genes overlapping with these CHG-DMRs were significantly enriched in DNA damage repair and nucleotide metabolism pathways. These results indicated that CHG methylation may be more sensitive than CG and CHH methylation in regulating the stability of the polyploid genome of B. napus. In addition, many genes involved in DNA damage repair, nucleotide metabolism, and cell cycle control were significantly differentially expressed between natural and synthetic rapeseeds. Our results highlight that the genes related to DNA repair and nucleotide metabolism display differential CHG methylation patterns between natural and synthetic polyploids and reveal the potential connection between the genomic instability of polyploid plants with DNA methylation defects and dysregulation of the DNA repair system. In addition, it was found that the maintenance of CHG methylation in B. napus might be partially regulated by MET1. Our study provides novel insights into the establishment and evolution of polyploid plants and offers a potential idea for improving the genomic stability of newly formed Brassica polyploids.

scholarly journals DNA Damage Repair and DNA Methylation in the Kidney

2019 ◽  
Vol 50 (2) ◽  
pp. 81-91 ◽  
Author(s):  
Kaori Hayashi ◽  
Akihito Hishikawa ◽  
Hiroshi Itoh
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Dna Repair ◽  
Methylation Status ◽  
Dna Damage Repair ◽  
Strand Break ◽  
Repair System ◽  
Damage Repair ◽  
Dna Double Strand Break ◽  
Cell Type Specific

The DNA repair system is essential for the maintenance of genome integrity and is mainly investigated in the areas of aging and cancer. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. Importance of DNA repair in the kidney is suggested by renal phenotypes caused by both genetic mutations in the DNA repair pathway and increased stimuli of DNA damage. Recently, we reported the importance of DNA double-strand break repair in glomerular podocytes and its involvement in the alteration of DNA methylation status, which regulates podocyte phenotypes. In this review, we summarize the roles of the DNA repair system in the kidneys and possible associations with altered kidney DNA methylation, which have been infrequently reported together. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.

C-Terminal Mutation of RUNX1 Deteriorates DNA Damage-Repair Response and Promotes the Development of Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 183-183
Author(s):  
Yusuke Satoh ◽  
Itaru Matsumura ◽  
Hirokazu Tanaka ◽  
Hironori Harada ◽  
Yuka Harada ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Myeloid Leukemia ◽  
Dna Damage Repair ◽  
Dna Lesions ◽  
Repair System ◽  
Loss Of Function ◽  
Dna Damage Signaling ◽  
Damage Repair ◽  
Lower Expression

Abstract Abstract 183 RUNX1 transcription factor regulates hematopoietic ontogeny and is a frequent target of gene rearrangements in hematological malignancies. In addition to gene rearrangements, loss-of-function mutations of RUNX1 have been found in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Mutations of RUNX1 have been detected in about 10–20% patients classified as MDS/AML (high-risk MDS and AML following MDS). Although loss-of-function mutations of RUNX1 cause leukemia together with additional cooperating events in mouse models, the mechanisms, by which impaired RUNX1 functions led to the subsequent genetic alterations, remain unclear. Because DNA damage-repair response has an important role for prevention of many types of tumors, including hematological malignancies, we analyzed the role for RUNX1 in DNA repair system. First, we stably expressed a dominant-negative mutant of RUNX1, RUNX1dC, in a murine myeloid cell line 32Dcl3. RUNX1dC lacks the C-terminal 225 amino acids, which was originally found in a patient with MDS and suppresses functions of wild-type (WT) RUNX1 by inhibiting its DNA binding activity. To analyze the roles for RUNX1 in the DNA repair system, we took advantage of in vitro DNA repair assays with DNA cross-linking agents in 32D-neo and 32D-RUNX1dC cells. Since the cells that recovered from DNA damage make colonies after cisplatin exposure, we can evaluate DNA repair ability of test cells with this assay. As a result, clonogenic ability of 32D-RUNX1dC was significantly decreased by the 2-hour exposure of cisplatin (10nM treatment: 93.4% reduction) compared to that of 32D-neo cell (10nM treatment: 58.6% reduction) (p=0.0006). In addition, 32D-RUNX1dC showed significantly lower clonogenic ability than 32D-neo after exposure to UV-B and gamma-ray, respectively. To evaluate DNA-damage accumulation in 32D-neo and 32D-RUNX1dC cells, we performed immunofluorescent microscopic analysis using monoclonal antibodies for (6–4) photoproducts (6–4 PPs) and cyclobutane pyrimidine dimers (CPDs), which are major products of DNA damage induced by UV-B. These types of DNA lesions are repaired by nucleotide excision repair (NER) system. After six hours from UV-B exposure, both 6–4 PPs and CPDs accumulated in 32D-RUNX1dC cells more abundantly than in 32D-neo cells. These results suggest that RUNX1dC attenuates NER in 32D cells, thereby leading to the sustained accumulations of DNA lesions after exposure to UV-B and cisplatin. To identify the molecule(s) involved in DNA-damage signaling, we profiled expression of 84 genes involved in DNA damage signaling by real-time RT-PCR array. The expression profiling revealed that RUNX1dC repressed Gadd45a, a regulator of NER system in 32D cells. Because genetic alteration of RUNX1 is supposed to occur at a HSC level in MDS and AML, we next evaluated whether RUNX1dC modifies Gadd45 expression in murine Lineage−Sca1+c-Kit+ (LSK) cells. As a result, RUNX1dC-transduced LSK cells showed significantly lower expression of Gadd45a and Gadd45b compared to Mock-transduced LSK cells. Luciferase reporter and chromatin immunoprecipitation assays showed that RUNX1 directly regulates Gadd45a expression via two RUNX1-binding sites neighboring to the p53-binding site in the intron 3 of the human Gadd45a gene. To confirm the roles for endogenous RUNX1 in NER system, we next performed RUNX1-knockdown experiments by short hairpin RNA (shRNA) -mediated gene silencing. RUNX1-shRNA-transduced 32D cells showed significantly lower expression of Gadd45a and Gadd45b than non-silensing-shRNA-transduced 32D cells. As expected, RUNX1-shRNA-transduced 32D cells showed significantly lower clonogenic ability after UV-B exposure than non-silensing-shRNA-transduced 32D cells (p=0.0008). These results suggest that endogenous RUNX1 regulates Gadd45 expression, thereby controlling NER system. Finally, we screened mRNA expression of Gadd45a in the samples from 23 MDS/AML patients, and found that its expression was significantly decreased in MDS/AML patients harboring RUNX1-C-terminal mutation compared to those with WT RUNX1 (p=0.0233). In summary, we here demonstrated that RUNX1 participates in the DNA damage-repair response through transcriptional regulation of Gadd45a. Our study suggests that the impaired RUNX1 function deteriorates NER system and may cause additional mutation(s), which are required for multi-step leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1289 ◽  
Author(s):  
Xing Bian ◽  
Wenchu Lin
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Repair ◽  
Predictive Biomarkers ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Repair System ◽  
Damage Repair ◽  
Repair Pathways

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

scholarly journals MAP4K1 functions as a tumor promotor and drug mediator for AML via modulation of DNA damage/repair system and MAPK pathway

EBioMedicine ◽  
2021 ◽  
Vol 69 ◽  
pp. 103441
Author(s):  
Qing Ling ◽  
Fenglin Li ◽  
Xiang Zhang ◽  
Shihui Mao ◽  
Xiangjie Lin ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mapk Pathway ◽  
Dna Damage Repair ◽  
Repair System ◽  
Damage Repair ◽  
Tumor Promotor

scholarly journals MicroRNA-146a-5p enhances radiosensitivity in hepatocellular carcinoma through replication protein A3-induced activation of the DNA repair pathway

2019 ◽  
Vol 316 (3) ◽  
pp. C299-C311 ◽  
Author(s):  
Jing Luo ◽  
Zhong-Zhou Si ◽  
Ting Li ◽  
Jie-Qun Li ◽  
Zhong-Qiang Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Repair ◽  
Replication Protein ◽  
Repair Pathway ◽  
Related Factors ◽  
Damage Repair ◽  
Hcc Cells

Hepatocellular carcinoma (HCC) is known for its high mortality rate worldwide. Based on intensive studies, microRNA (miRNA) expression functions in tumor suppression. Therefore, we aimed to evaluate the contribution of miR-146a-5p to radiosensitivity in HCC through the activation of the DNA damage repair pathway by binding to replication protein A3 (RPA3). First, the limma package of R was performed to differentially analyze HCC expression chip, and regulative miRNA of RPA3 was predicted. Expression of miR-146a-5p, RPA3, and DNA damage repair pathway-related factors in tissues and cells was determined. The effects of radiotherapy on the expression of miR-146a-5p and RPA3 as well as on cell radiosensitivity, proliferation, cell cycle, and apoptosis were also assessed. The results showed that there exists a close correlation between miR-146a and the radiotherapy effect on HCC progression through regulation of RPA3 and the DNA repair pathway. The positive rate of ATM, pCHK2, and Rad51 in HCC tissues was higher when compared with that of the paracancerous tissues. SMMC-7721 and HepG2 cell proliferation were significantly inhibited following 8 Gy 6Mv dose. MiR-146a-5p restrained the expression of RPA3 and promoted the expression of relative genes associated with the DNA repair pathway. In addition, miR-146a-5p overexpression suppresses cell proliferation and enhances radiosensitivity and cell apoptosis in HCC cells. In conclusion, the present study revealed that miR-146a-5p could lead to the restriction of proliferation and the promotion of radiosensitivity and apoptosis in HCC cells through activation of DNA repair pathway and inhibition of RPA3.

Deeper Insight in Metastatic Cancer progression;Epithelial-to-Mesenchymal Transition and Genomic Instability: implications on treatment resistance

2021 ◽  
Vol 21 ◽  
Author(s):  
Kenneth Omabe ◽  
Sandra Uduituma ◽  
David Igwe ◽  
Maxwell Omabe
Keyword(s):  
Dna Damage ◽  
Cancer Treatment ◽  
Epithelial To Mesenchymal Transition ◽  
Dna Damage Repair ◽  
Treatment Resistance ◽  
Therapy Resistance ◽  
Cellular Reprogramming ◽  
Repair System ◽  
Mesenchymal Transition ◽  
Damage Repair

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

scholarly journals Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair

Cell Reports ◽  
2019 ◽  
Vol 28 (5) ◽  
pp. 1136-1143.e4 ◽  
Author(s):  
Shujun Fu ◽  
Zhi Li ◽  
Lanbo Xiao ◽  
Wenfeng Hu ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Glutamine Synthetase ◽  
Radiation Resistance ◽  
Dna Damage Repair ◽  
Nucleotide Metabolism ◽  
Damage Repair

Bortezomib Enhances Melphalan Response by Altering Fanconi Anemia (FA)/BRCA Pathway Expression and Function.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 840-840 ◽  
Author(s):  
Danielle N. Yarde ◽  
Lori A. Hazlehurst ◽  
Vasco A. Oliveira ◽  
Qing Chen ◽  
William S. Dalton
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Repair ◽  
Low Dose ◽  
Dna Damage Repair ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Multiple Myeloma Cell ◽  
Damage Repair ◽  
Pre Treatment

Abstract The FA/BRCA pathway is involved in DNA damage repair and its importance in oncogenesis has only recently been implicated. Briefly, 8 FA/BRCA pathway family members facilitate the monoubiquitination of FANCD2. Upon monoubiquitination, FANCD2 translocates to the DNA repair foci where it interacts with other proteins to initiate DNA repair. Previously, we reported that the FA/BRCA pathway is upregulated in multiple myeloma cell lines selected for resistance to melphalan (Chen, et al, Blood 2005). Further, reducing FANCF in the melphalan resistant 8226/LR5 myeloma cell line partially reversed resistance, whereas overexpressing FANCF in the drug sensitive 8226/S myeloma line conferred resistance to melphalan. Others have reported, and we have also verified, that bortezomib enhances melphalan response in myeloma cells; however, the mechanism of enhanced melphalan activity in combination with bortezomib has not been reported. Based on our observation that the FA/BRCA pathway confers melphalan resistance, we hypothesized that bortezomib enhances melphalan response by targeting FA/BRCA DNA damage repair pathway genes. To investigate this hypothesis, we first analyzed FA/BRCA gene expression in 8226/S and 8226/LR5 cells treated with bortezomib, using a customized microfluidic card (to detect BRCA1, BRCA2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, RAD51 and RAD51C) and q-PCR. Interestingly, we found that low dose (5nM) bortezomib decreased many FA/BRCA pathway genes as early as 2 hours, with maximal decreases seen at 24 hours. Specifically, 1.5- to 2.5-fold decreases in FANCA, FANCC, FANCD2, FANCE and RAD51C were seen 24 hours post bortezomib exposure. Moreover, pre-treatment of myeloma cells with low dose bortezomib followed by melphalan treatment revealed a greater than 2-fold reduction in FANCD2 gene expression levels. We also found that melphalan treatment alone enhanced FANCD2 protein expression and activation (monoubiquitination), whereas the combination treatment of bortezomib followed by melphalan decreased activation and overall expression of FANCD2 protein. Taken together, these results suggest that bortezomib enhances melphalan response in myeloma by targeting the FA/BRCA pathway. Further understanding of the role of the FA/BRCA pathway in determining melphalan response may allow for more customized and effective treatment of myeloma.

ATM as a biomarker for DNA damage repair deficiency in pancreatic ductal adenocarcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 308-308
Author(s):  
Talia Golan ◽  
Sharon Halparin ◽  
Chani Stossel ◽  
Maria Raitses-Gurevich ◽  
Dikla Atias ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Protein Expression ◽  
Dna Damage Repair ◽  
Personal History ◽  
Nuclear Staining ◽  
Repair Pathway ◽  
Damage Repair ◽  
History Of ◽  
Atm Protein

308 Background: Approximately 15% of PDAC tumors display DNA damage repair (DDR) deficiency. Germline BRCA (gBRCA) mutation serves as a robust biomarker for the DDR deficiency. A subset of patients displays a similar clinical phenotype but lack the gBRCA mutation. Identification of these BRCA-like subset of patients remains a challenge and an alternative approach may include DDR functional assays. Here we suggest loss of the ATM protein as one of the biomarkers for the identification of the DDR deficiency signature in PDAC. Methods: Patients were identified from the Sheba pancreatic cancer database based on strong family/personal history of BRCA- associated cancers or a durable response to platinum containing regimens ( ≥ 6 month) or harboring germline/somatic mutations in the DNA repair pathway (excluding gBRCA mutation). Archival FFPE blocks of primary tumors/metastatic lesions were used to explore ATM protein expression by IHC. Nuclear staining was regarded as positive. Tumor infiltrating lymphocytes served as an internal positive control. ATM loss was defined as less than10% neoplastic nuclear staining at any intensity in the presence of positive lymphocytes staining. Results: We identified 53 patients with DDR deficiency phenotype between 2014-2016 from the Sheba PDAC database (n = 250). Median age at diagnosis was 65 years (46-81) and the majority were female (62%). 47% were diagnosed at stage I/II and 53% stage IV. In the subgroup of patients with DDR deficiency phenotype, 55% displayed a family history of BRCA-associated cancers, 19% had a personal history of malignancy and23% had known mutation in DNA repair pathway. 23/53 identified subjects have been analyzed to date. We identified 52% loss of ATM in the analyzed group (n = 23). Conclusions: Loss of ATM in an unselected PDAC population is 12% (H. Kim et al, 2014). Our data demonstrate that 52% of the highly selected subgroup of PDAC patients (DDR deficiency phenotype) was found to have loss of ATM protein expression, suggesting it to be one of the biomarker for DDR signature. Identification of these patients, based on ATM protein expression profile may lead to personalized treatment options.

Retrospective analysis of patients using olaparib (O) in pancreatic cancer (PC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 389-389
Author(s):  
Erkut Hasan Borazanci ◽  
Carol Guarnieri ◽  
Susan Haag ◽  
Ronald Lee Korn ◽  
Courtney Edwards Snyder ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Retrospective Analysis ◽  
Pearson Correlation ◽  
Brca2 Mutation ◽  
Dna Damage Repair ◽  
Parp Inhibitors ◽  
Damage Repair ◽  
Repair Deficiency

389 Background: Molecular analysis has revealed four subtypes of PC giving clinicians further insight into treating this deadly disease. One subtype that was elucidated termed “unstable” is significant for the presence of DNA damage repair deficiency and can be targeted therapeutically. One such therapy, O, from the drug class poly ADP ribose polymerase (PARP) inhibitors, has already been FDA approved for individuals with BRCA mutated ovarian cancers. We performed a retrospective analysis on patients with PC treated at a single institution who have DNA damage repair deficiency mutations and have been treated with O. Methods: A chart review identified pancreatic cancer patients with DNA repair pathway mutations who were treated with O. The primary objective examined ORR in patients with PC with DNA repair mutations receiving O. Secondary objectives included tolerability, overall survival (OS), CA 19-9 change, and changes in quantitative textural analysis (QTA) on CT. Results: 11 individuals were identified, 5 carriers of a pathogenic germline (g) BRCA2 mutation, 1 carrier of a pathogenic g ATM mutation, 1 carrier of a pathogenic g BRCA1 mutation. Variants of uncertain significance (VUS) included 1 g ATM mutation, 1 g PALB2 mutation, 1 somatic (s) C11orf30 mutation, and 1 s BRCA2 mutation. Median age at diagnosis was 59, with 4 M and 7 F. No patients met criteria for familial PC and 7 had a family history consistent for breast and ovarian cancer syndrome. All individuals had metastatic PC and had progressed on at least 1 line of systemic therapy. ORR was 18%. Median time of therapy on O was 5 months (mo) (Range 1.4 to 29.567 mo) with 5 of the individuals still undergoing treatment at the time of analysis. Mean OS was 12.35 mo, 9 of the 11 individuals still alive. QTA of baseline CTs from subjects with liver (8/11) and pancreatic tumors (7/11) revealed a strong association between lesion texture and OS (Pearson correlation coefficient (PCC): hepatic mets = 0.952, p = 0.0003) and time on O (PCC: panc lesions = 0.889, p = 0.006). Conclusions: In individuals with metastatic PC with mutations involved in DNA repair, O may provide clinical benefit. QTA of individual tumors may allow for additional information that predicts outcomes to PARP inhibitors in this population.

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