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Targeting DNA repair for cancer treatment: Lessons from PARP inhibitor trials
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作者 DHANYA K.NAMBIAR DEEPALI MISHRA RANA P.SINGH 《Oncology Research》 SCIE 2023年第4期405-421,共17页
Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer cells.However,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation ... Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer cells.However,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation therapy.Thus,PARP-1 represents an important target in multiple cancer types,including prostate cancer.PARP is a nuclear enzyme essential for single-strand DNA breaks repair.Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)pathway.This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications.We focused on the use of PARP inhibitors in various cancers,including prostate cancer.We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors. 展开更多
关键词 PARP inhibitors Synthetic lethality dna repair BRCA mutations
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Homologous recombination in DNA repair and DNA damage tolerance 被引量:30
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作者 Xuan Li Wolf-Dietrich Heyer 《Cell Research》 SCIE CAS CSCD 2008年第1期99-113,共15页
Homologous recombination (HR) comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks (DSBs) and interstrand crosslinks (ICLs). In addition, recombination provides c... Homologous recombination (HR) comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks (DSBs) and interstrand crosslinks (ICLs). In addition, recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, contributing to tolerance of DNA damage. A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key reactions that typify HR: homology search and DNA strand invasion. The diverse functions of recombination are reflected in the need for context-specific factors that perform supplemental functions in conjunction with the core proteins. The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer etiology. Mutations in the BRCA2 recombination gene cause predisposition to breast and ovarian cancer as well as Fanconi anemia, a cancer predisposition syndrome characterized by a defect in the repair of DNA interstrand crosslinks. The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating cells by the direct or indirect induction of DNA lesions that are substrates for recombination pathways. This review focuses on mechanistic aspects of HR relating to DSB and ICL repair as well as replication fork support. 展开更多
关键词 dna repair double-strand breaks genome stability homologous recombination interstrand crosslinks stalled replication forks
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Assessment of Human DNA Repair (NER) Capacity With DNA Repair Rate (DRR) by Comet Assay 被引量:5
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作者 WEIZHENG JI-LIANGHE +2 位作者 LI-PENJIN JIAN-LINLOU BAO-HONGWANG 《Biomedical and Environmental Sciences》 SCIE CAS CSCD 2005年第2期117-123,共7页
Objective Alkaline comet assay was used to evaluate DNA repair (nucleotide excision repair, NER) capacity of human fresh lymphocytes from 12 young healthy non-smokers (6 males and 6 females). Methods Lymphocytes were ... Objective Alkaline comet assay was used to evaluate DNA repair (nucleotide excision repair, NER) capacity of human fresh lymphocytes from 12 young healthy non-smokers (6 males and 6 females). Methods Lymphocytes were exposed to UV-C (254 nm) at the dose rate of 1.5 J/m2/sec. Novobiocin (NOV) and aphidicolin (APC), DNA repair inhibitors, were utilized to imitate the deficiency of DNA repair capacity at the incision and ligation steps of NER. Lymphocytes from each donor were divided into three grougs: UVC group, UVC plus NOV group, and UVC plus APC group. DNA single strand breaks were detected in UVC irradiated cells incubated for 0, 30, 60, 90, 120, 180, and 240 min after UVC irradiation. DNA repair rate (DRR) served as an indicator of DNA repair capacity. Results The results indicated that the maximum DNA damage (i.e. maximum tail length) in the UVC group mainly appeared at 90 min. The ranges of DRRs in the UVC group were 62.84%-98.71%. Average DRR value was 81.84%. The DRR difference between males and females was not significant (P<0.05). However, the average DRR value in the UVC plus NOV group and the UVC plus APC group was 52.98% and 39.57% respectively, which were significantly lower than that in the UVC group (P<0.01). Conclusion The comet assay is a rapid, simple and sensitive screening test to assess individual DNA repair (NER) capacity. It is suggested that the time to detect DNA single strand breaks in comet assay should include 0 (before UV irradiation), 90 and 240 min after exposure to 1.5 J·m-2 UVC at least. The DRR, as an indicator, can represent the individual DNA repair capacity in comet assay. 展开更多
关键词 dna repair capacity Comet assay UVC NOVOBIOCIN APHIDICOLIN
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A brief history of the DNA repair field 被引量:7
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作者 Errol C Friedberg 《Cell Research》 SCIE CAS CSCD 2008年第1期3-7,共5页
The history of the repair of damaged DNA can be traced to the mid-1930s. Since then multiple DNA repair mechanisms, as well as other biological responses to DNA damage, have been discovered and their regulation has be... The history of the repair of damaged DNA can be traced to the mid-1930s. Since then multiple DNA repair mechanisms, as well as other biological responses to DNA damage, have been discovered and their regulation has been studied. This article briefly recounts the early history of this field. 展开更多
关键词 dna repair biological responses to dna damage ultraviolet light excision repair enzymatic photoreactivation mismatch repair dna damage tolerance recombination
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DNA repair and synthetic lethality 被引量:2
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作者 Gong-she Guo Feng-mei Zhang +3 位作者 Rui-jie Gao Robert Delsite Zhi-hui Feng Simon N. Powell 《International Journal of Oral Science》 SCIE CAS CSCD 2011年第4期176-179,共4页
Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particu... Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particular homologous recombination (HR), are highly sensitive to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR-defective tumor cells. 展开更多
关键词 dna repair homologous recombination synthetic lethality BRCA Rad52
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Association Between Polymorphisms of DNA Repair Gene XRCC1 and DNA Damage in Asbestos-Exposed Workers 被引量:1
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作者 XIAO-HONG ZHAO CUANG JIA +4 位作者 YONG-QUAN LIU SHAO-WEI LIU LEI YAN YU JIN NIAN LIU 《Biomedical and Environmental Sciences》 SCIE CAS CSCD 2006年第3期232-238,共7页
Objective To compare the asbestos-induced DNA damage and repair capacities of DNA damage between 104 asbestosexposed workers and 101 control workers in Qingdao City of China and to investigate the possible association... Objective To compare the asbestos-induced DNA damage and repair capacities of DNA damage between 104 asbestosexposed workers and 101 control workers in Qingdao City of China and to investigate the possible association between polymorphisms in codon 399 of XRCC1 and susceptibility to asbestosis. Methods DNA damage levels in peripheral blood lymphocytes were determined by comet assay, and XRCC1 genetic polymorphisms of DNA samples from 51 asbestosis cases and 53 non-asbestosis workers with a similar asbestos exposure history were analyzed by PCR/RFLP. Results The basal comet scores (3.95±2.95) were significantly higher in asbestos-exposed workers than in control workers (0.10±0.28). After 1 h H2O2 stimulation, DNA damage of lymphocytes exhibited different increases. After a 4 h repair period, the comet scores were 50.98±19.53 in asbestos-exposed workers and 18.32±12.04 in controls. The residual DNA damage (RD) was significantly greater (P〈0.01) in asbestos-exposed workers (35.62%) than in controls (27.75%). XRCC1 genetic polymorphism in 104 asbestos-exposed workers was not associated with increased risk of asbestosis. But compared with polymorphisms in the DNA repair gene XRCC1 (polymorphisms in codon 399) and the DNA damage induced by asbestos, the comet scores in asbestosis cases with Gin/Gin, Gln/Arg, and Arg/Arg were 40.26±18.94, 38.03±28.22, and 32.01±11.65, respectively, which were higher than those in non-asbestosis workers with the same genotypes (25.58±11.08, 37.08±14.74, and 29.38±10.15). There were significant differences in the comet scores between asbestosis cases and non-asbestosis workers with Gin/Gin by Student's t-test (P〈0.05 or 0.01). The comet scores were higher in asbestosis workers with Gin/Gin than in those with Arg/Arg and in non-asbestosis workers exposed to asbestos, but without statistically significant difference. Conclusions Exposure to asbestos may be related to DNA damage or the capacity of cells to repair H2O2-induced DNA damage. DNA repair gene XRCC 1 codon 399 may be responsible for the inter-individual susceptibility in DNA damage and repair capacities. 展开更多
关键词 Asbestos ASBESTOSIS dna damage XRCC 1 dna repair POLYMORPHISMS Comet assays
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Neuronal effects of SP600125 pretreatment in a rat model of cerebral ischemia/reperfusion injury Inhibited down-regulation of DNA repair protein 被引量:1
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作者 Ning Wang Rongliang Xue +4 位作者 Fengzhen Yao Jiaxuan He Jianrui Lu Pengbo Zhang Gang Wu 《Neural Regeneration Research》 SCIE CAS CSCD 2009年第12期1055-1061,共7页
BACKGROUND: Recent studies have shown that the selective inhibitor of c-Jun N-terminal kinases (JNKs) signaling pathway, SP600125, exhibits neuronal protective effects in a rat model of brain ischemia/reperfusion. ... BACKGROUND: Recent studies have shown that the selective inhibitor of c-Jun N-terminal kinases (JNKs) signaling pathway, SP600125, exhibits neuronal protective effects in a rat model of brain ischemia/reperfusion. OBJECTIVE: To determine the mechanisms of neuroprotective effects of SP600125 in a rat model of brain ischemia/reperfusion, and determine the role of the JNK signaling pathway in SP600125-induced effects. DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed at the Animal Experiment Center, Medical School of Xi'an Jiaotong University from June 2007 to September 2008. MATERIALS: SP600125 was provided by Biosource, USA; rabbit anti-phospho-JNK (Thr183/Tyr185) polyclonal antibody from Cell Signaling Technology, USA; rabbit anti-X-ray repair cross-complementing protein 1 (XRCC1) and anti-Ku70 polyclonal antibodies from Santa Cruz Biotechnology, USA; and TUNEL kit from Beijing Huamei Biology, China. METHODS: A total of 108 male, 4-month-old, Sprague Dawley rats were randomly assigned to three groups, with 36 rats per group. The sham operation group and ischemia/reperfusion group (I/R group) were intracerebroventricularly injected with 10 μL 1% DMSO. The SP600125-treated group (pre-SP group) was given 10 μL SP600125 (3 μg/μL). Thirty minutes later, brain ischemia was induced in the I/R and pre-SP groups using the four-vessel occlusion method. Specifically, whole brain ischemia was induced for 6 minutes, and the clips were released to restore carotid artery blood flow. Rats from each group were observed at 2, 6, 12, 24, 48, and 72 hours, with 6 rats for each time point. The sham operation group was treated with the same surgical exposure procedures, with exception of occlusion of the carotid artery. MAIN OUTCOME MEASURES: Hematoxylin-eosin staining was used to observe neuronal survival in the hippocampal CA1 region, TUNEL was used to detect apoptosis in the hippocampal CA1 region, and immunohistochemistry was used to detect expression of phospho-JNK, XRCC1, and Ku70. RESULTS: Following brain ischemia/reperfusion, neuronal survival significantly decreased, and the number of apoptotic cells significantly increased (P 〈 0.01). Compared with the I/R group, neuronal survival significantly increased in the pre-SP group, and the number of apoptotic cells significantly decreased (P 〈 0.01). Expression of phospho-JNK increased, and XRCC1 and Ku70 significantly decreased (P 〈 0.05) following ischemia/reperfusion. Compared with the I/R group, expression of phospho-JNK decreased, and XRCC1 and Ku70 significantly increased in the pre-SP group (P 〈 0.05). Correlation analysis revealed an inverse correlation between phospho-JNK gray value and XRCC1 and Ku70 gray values in the hippocampal CA1 region (r = -0.983, -0.953, P 〈 0.01). CONCLUSION: SP600125 treatment decreased apoptosis induced by global brain ischemia/reperfusion in the rat hippocampal CA1 region. Results suggested that the neuroprotective effects were due to inhibited phosphorylation of JNK and reduced down-regulation of XRCC1 and Ku70. 展开更多
关键词 ischemia/reperfusion injury apoptosis c-Jun N-terminal kinases dna repair protein X-ray repair cross-complementing protein 1 KU70
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Evolving insights:how DNA repair pathways impact cancer evolution 被引量:1
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作者 Jiadong Zhou Xiao Albert Zhou +1 位作者 Ning Zhang Jiadong Wang 《Cancer Biology & Medicine》 SCIE CAS CSCD 2020年第4期805-827,共23页
Viewing cancer as a large,evolving population of heterogeneous cells is a common perspective.Because genomic instability is one of the fundamental features of cancer,this intrinsic tendency of genomic variation leads ... Viewing cancer as a large,evolving population of heterogeneous cells is a common perspective.Because genomic instability is one of the fundamental features of cancer,this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation,development,metastasis,and relapse.With the increased mutation rate and abundant diversity of the gene pool,this heterogeneity leads to cancer evolution,which is the major obstacle in the clinical treatment of cancer.Cells rely on the integrity of DNA repair machineries to maintain genomic stability,but these machineries often do not function properly in cancer cells.The deficiency of DNA repair could contribute to the generation of cancer genomic instability,and ultimately promote cancer evolution.With the rapid advance of new technologies,such as single-cell sequencing in recent years,we have the opportunity to better understand the specific processes and mechanisms of cancer evolution,and让s relationship with DNA repair.Here,we review recent findings on how DNA repair affects cancer evolution,and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications. 展开更多
关键词 dna repair cancer evolution intratumor heterogeneity genomic instability drug resistance
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Expressions of genes related to genome stability and DNA repair in nasopharyngeal carcinoma clustering families 被引量:1
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作者 Xiaojun Zhou Daofa Tian +4 位作者 Shizhen Wang Yan Ruana Baoshan Qju Lijuan Zhang Biaoqing Lu 《The Chinese-German Journal of Clinical Oncology》 CAS 2009年第12期713-718,共6页
Objective: The aim of the study was to observe the expressions of genes related to genome stability and DNA repair in the members of nasopharyngeal carcinoma (NPC) clustedng families. Methods: In the Zhongshan Cit... Objective: The aim of the study was to observe the expressions of genes related to genome stability and DNA repair in the members of nasopharyngeal carcinoma (NPC) clustedng families. Methods: In the Zhongshan City where there is highly incidence rate of NPC, we chose the members of the NPC clustering families as objects, and the patients of nasopharyngitis and NPC as the control group. We isolated the RNA from the nasopharyngeal tissue, and synthesized its cRNA, the genome stability and DNA repair genes chip technique, chemiluminescent detection and real-time fluorescence quantita- tive technique were used to examine the genome stability and DNA repair genes in the nasopharyngeal tissue. Results: More genome stability and DNA repair genes were up-regulated in the members of the NPC clustering families than the NPC patients, and the range of up-regulated was high, with the over up-regulated 100 times genes including TEP1, MSH4, PMS2LI. Fewer genome stability and DNA repair genes were down-regulated in the members of the NPC clustering families than the NPC patients, the ubiquitin genes almost were down-regulated, the results also could be confirmed by real-time fluorescence quantitative PCR. Conclusion: There are specially expression character of genome stability and DNA repair genes in the members of NPC clustering families. 展开更多
关键词 nasopharyngeal carcinoma (NPC) cancer clustering families genome stability and dna repair gene gene chip real-time fluorescence quantitative PCR UBIQUITIN
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Translational regulation of DNA repair systems by eIF3a in cancer chemotherapeutic response
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作者 CHEN Juan CUI Jia-jia +3 位作者 ZHANG Jian-ting ZHOU Hong-hao LIU Zhao-qian YIN Ji-ye 《中国药理学与毒理学杂志》 CAS CSCD 北大核心 2016年第10期1050-1051,共2页
OBJECTIVE To investigate the role of e IF3a in the regulation of DNA repair pathways in cancer chemotherapeutic response.METHODS Immunohistochemistry was used to determine the expression of e IF3a in lung and breast c... OBJECTIVE To investigate the role of e IF3a in the regulation of DNA repair pathways in cancer chemotherapeutic response.METHODS Immunohistochemistry was used to determine the expression of e IF3a in lung and breast cancer tissues followed by association analysis of e IF3a expression with patient′s response to chemotherapy.Ectopic overexpression and RNA interference knockdown of e IF3a were carried out in NIH3T3and H1299 cell lines,respectively,to determine the effect of altered e IF3a expression on cellular response to chemotherapeutic drugs by using MTT assay.The DNA repair capacity of these cells was evaluated by using host-cell reactivation,NHEJ and HR assay.Real-time reverse transcriptase PCR and Western Blot analyses were carried out to determine the effect of e IF3a on the DNA repair genes by using cells with altered e IF3a expression.RESULTS e IF3a expression associates with response of lung and breast cancer patients to platinum and anthracycline.e IF3a knockdown or overexpression,respectively,increased and decreased the cellular resistance to cisplatin and anthracycline anticancer drugs,DNA repair activity,and expression of NER and NHEJ DNA repair proteins.CONCLUSION e IF3a plays an important role in regulating the expression of NER and NHEJ DNA repair proteins which,in turn,contributes to cellular response to DNA-damaging anticancer drugs and patients′response to platinum and anthracycline chemotherapy. 展开更多
关键词 eIF3a dna repair translation regulation PLATINUM ANTHRACYCLINE cancer chemotherapy
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Molecular epidemiology of DNA repair gene polymorphisms and head and neck cancer
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作者 Meilin Wang Haiyan Chu +1 位作者 Zhengdong Zhang Qingyi Wei 《The Journal of Biomedical Research》 CAS 2013年第3期179-192,共14页
Although tobacco and alcohol consumption are two common risk factors of head and neck cancer (HNC), other specific etiologic causes, such as viral infection and genetic susceptibility factors, remain to be understoo... Although tobacco and alcohol consumption are two common risk factors of head and neck cancer (HNC), other specific etiologic causes, such as viral infection and genetic susceptibility factors, remain to be understood. Hu- man DNA is often damaged by numerous endogenous and exogenous mutagens or carcinogens, and genetic vari- ants in interaction with environmental exposure to these agents may explain interindividual differences in HNC risk. Single nucleotide polymorphisms (SNPs) in genes involved in the DNA damage-repair response are reported to be risk factors for various cancer types, including HNC. Here, we reviewed epidemiological studies that have assessed the associations between HNC risk and SNPs in DNA repair genes involved in base-excision repair, nucleotide-excision repair, mismatch repair, double-strand break repair and direct reversion repair pathways. We found, however, that only a few SNPs in DNA repair genes were found to be associated with significantly in- creased or decreased risk of HNC, and, in most cases, the effects were moderate, depending upon locus-locus in- teractions among the risk SNPs in the pathways. We believe that, in the presence of exposure, additional pathway- based analyses of DNA repair genes derived from genome-wide association studies (GWASs) in HNC are needed. 展开更多
关键词 dna repair molecular epidemiology head and neck cancer genetic variation genome-wide asso-ciation study
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Association between the DNA Repair Gene Polymorphisms and Lung Cancer in Turkish Population
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作者 Nuran Dingil Ziyaeddin Inan Ayşegül Şentürk 《Advances in Lung Cancer》 2022年第2期15-29,共15页
Introduction: DNA repair enzymes continuously monitor DNA to correct damaged nucleotide residues generated by exposure to environmental mutagenic and cytotoxic compounds or carcinogens. Our objective was to investigat... Introduction: DNA repair enzymes continuously monitor DNA to correct damaged nucleotide residues generated by exposure to environmental mutagenic and cytotoxic compounds or carcinogens. Our objective was to investigate the association among XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD-ERCC2 (Lys751Gln), APE1 (Asp241Glu), PARP-ADPRT (Val762Ala) DNA repair gene polymorphisms and lung cancer in Turkish population. Materials and Methods: Our patient group consists of 90 patients with lung cancer and the control group had 100 healthy individuals all of those smoking. DNA was extracted using the whole blood samples. PCR- RFLP technique was used to investigate the polymorphisms on target genes. Results: There was no significant difference in the genotype distributions of XPD Lys751Gln, XRCC1 Arg194Trp, XRCC3 Thr241Met, APE1 Asp241Glu between lung cancer patients and controls for each polymorphism (p > 0.05). However, there was a significant difference between the genotype distributions of XRCC1 Arg399Gln, and PARP Val762Ala in patients and the control group (p > 0.05). Discussion: Only the polymorphisms of XRCC1 codon 399 and PARP Val762Ala alleles are associated with the risk of lung cancer. Other genotypes were not related to lung cancer. 展开更多
关键词 Lung Cancer POLYMORPHISM dna repair Genes Turkish Population PCR-RFLP
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Epigenetic regulation of DNA repair machinery in Helicobacter pylori-induced gastric carcinogenesis 被引量:20
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作者 Juliana Carvalho Santos Marcelo Lima Ribeiro 《World Journal of Gastroenterology》 SCIE CAS 2015年第30期9021-9037,共17页
Although thousands of DNA damaging events occur in each cell every day,efficient DNA repair pathways have evolved to counteract them. The DNA repair machinery plays a key role in maintaining genomic stability by avoid... Although thousands of DNA damaging events occur in each cell every day,efficient DNA repair pathways have evolved to counteract them. The DNA repair machinery plays a key role in maintaining genomic stability by avoiding the maintenance of mutations. The DNA repair enzymes continuously monitor the chromosomes to correct any damage that is caused by exogenous and endogenous mutagens. If DNA damage in proliferating cells is not repaired because of an inadequate expression of DNA repair genes,it might increase the risk of cancer. In addition to mutations,which can be either inherited or somatically acquired,epigenetic silencing of DNA repair genes has been associated with carcinogenesis. Gastric cancer represents the second highest cause of cancer mortality worldwide. The disease develops from the accumulation of several genetic and epigenetic changes during the lifetime. Among the risk factors,Helicobacter pylori(H. pylori) infection is considered the main driving factor to gastric cancer development. Thus,in this review,we summarize the current knowledge of the role of H. pylori infection on the epigenetic regulation of DNA repair machinery in gastric carcinogenesis. 展开更多
关键词 HELICOBACTER PYLORI dna repair EPIGENETIC dna methylation Gastric cancer HISTONE modification
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Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer 被引量:7
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作者 Shih-Hung Yang Ting-Chun Kuo +7 位作者 Hsu Wu Jhe-Cyuan Guo Chiun Hsu Chih-Hung Hsu Yu-Wen Tien Kun-Huei Yeh Ann-Lii Cheng Sung-Hsin Kuo 《World Journal of Gastroenterology》 SCIE CAS 2016年第32期7275-7288,共14页
Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair... Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2 AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation(radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to coadministration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA doublestrand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit(DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2 A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer. 展开更多
关键词 RADIOTHERAPY PANCREATIC cancer dna damage dna repair Molecular TARGETS
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Epigenetic reduction of DNA repair in progression to gastrointestinal cancer 被引量:2
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作者 Carol Bernstein Harris Bernstein 《World Journal of Gastrointestinal Oncology》 SCIE CAS 2015年第5期30-46,共17页
Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal(GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. Howev... Deficiencies in DNA repair due to inherited germ-line mutations in DNA repair genes cause increased risk of gastrointestinal(GI) cancer. In sporadic GI cancers, mutations in DNA repair genes are relatively rare. However, epigenetic alterations that reduce expression of DNA repair genes are frequent in sporadic GI cancers. These epigenetic reductions are also found in field defects that give rise to cancers. Reduced DNA repair likely allows excessive DNA damages to accumulate in somatic cells. Then either inaccurate translesion synthesis past the un-repaired DNA damages or error-prone DNA repair can cause mutations. Erroneous DNA repair can also cause epigenetic alterations(i.e., epimutations, transmitted through multiple replication cycles). Some of these mutations and epimutations may cause progression to cancer. Thus, deficient or absent DNA repair is likely an important underlying cause of cancer. Whole genome sequencing of GI cancers show that between thousands to hundreds of thousands of mutations occur in these cancers. Epimutations that reduce DNA repair gene expression and occur early in progression to GI cancers are a likely source of this high genomic instability. Cancer cells deficient in DNA repair are more vulnerable than normal cells to inactivation by DNA damaging agents. Thus, some of the most clinically effective chemotherapeutic agents in cancer treatment are DNA damaging agents, and their effectiveness often depends on deficient DNA repair in cancer cells. Recently, at least 18 DNA repair proteins, each active in one of six DNA repair pathways, were found to be subject to epigenetic reduction of expression in GI cancers. Different DNA repair pathways repair different types of DNA damage. Evaluation of which DNA repair pathway(s) are deficient in particular types of GI cancer and/or particular patients may prove useful in guiding choice of therapeutic agents in cancer therapy. 展开更多
关键词 EPIGENETIC dna damage dna repair dna repair deficiency DISORDERS Epimutation Genomicinstability GERM-LINE mutation MicroRNAs Precancerousconditions GASTROINTESTINAL cancer
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Ovarian cancer and DNA repair: DNA ligase IV as a potential key 被引量:2
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作者 Joana Assis Deolinda Pereira Rui Medeiros 《World Journal of Clinical Oncology》 CAS 2013年第1期14-24,共11页
Ovarian cancer(OC)is the sixth most common cancer and the seventh cause of death from cancer in women.The etiology and the ovarian carcinogenesis still need clarification although ovulation may be determinant due to i... Ovarian cancer(OC)is the sixth most common cancer and the seventh cause of death from cancer in women.The etiology and the ovarian carcinogenesis still need clarification although ovulation may be determinant due to its carcinogenic role in ovarian surface epithelium.The link between ovarian carcinogenesis and DNA repair is well established and it became clear that alterations in DNA damage response may affect the risk to develop OC.Polymorphisms are variations in the DNA sequence that exist in normal individuals of a population and are capable to change,among other mechanisms,the balance between DNA damage and cellular response.Consequently,genetic variability of the host has a great role in the development,progression and consequent prognosis of the oncologic patient as well as in treatment response.Standard treatment for OC patients is based on cytoreductive surgery,followed by chemotherapy with a platinum agent and a taxane.Although 80%of the patients respond to the first-line therapy,the development of resistance is common although the mechanisms underlying therapy failure remain mostly unknown.Because of their role in oncology,enzymes involved in the DNA repair pathways,like DNA Ligase IV(LIG4),became attractive study targets.It has been reported that variations in LIG4 activity can lead to a hyper-sensitivity to DNA damage,deregulation of repair and apoptosis mechanisms,affecting the susceptibility to cancer development and therapy response.To overcome resistance mechanisms,several investigations have been made and the strategy to target crucial molecular pathways,such as DNA repair,became one of the important areas in clinical oncology.This review aims to elucidate the link between DNA repair and OC,namely which concerns the role of LIG4 enzyme,and how genetic polymorphisms in LIG4 gene can modulate the activity of the enzyme and affect the ovarian carcinogenesis and treatment response.Moreover,we try to understand how LIG4 inhibition can be a potential contributor for the development of new cancer treatment strategies. 展开更多
关键词 OVARIAN Cancer dna repair dna LIGASE IV POLYMORPHISMS SUSCEPTIBILITY Treatment response
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New insights into tumor dormancy:Targeting DNA repair pathways 被引量:1
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作者 Elizabeth B Evans Shiaw-Yih Lin 《World Journal of Clinical Oncology》 CAS 2015年第5期80-88,共9页
Over the past few decades, major strides have advanced the techniques for early detection and treatment of cancer. However, metastatic tumor growth still accounts for the majority of cancer-related deaths worldwide. I... Over the past few decades, major strides have advanced the techniques for early detection and treatment of cancer. However, metastatic tumor growth still accounts for the majority of cancer-related deaths worldwide. In fact, breast cancers are notorious for relapsing years or decades after the initial clinical treatment, and this relapse can vary according to the type of breast cancer. In estrogen receptor-positive breast cancers, late tumor relapses frequently occur whereas relapses in estrogen receptor-negative cancers or triple negative tumors arise early resulting in a higher mortality risk. One of the main causes of metastasis is tumor dormancy in which cancer cells remain concealed, asymptomatic, and untraceable over a prolonged period of time. Under certain conditions, dormant cells can re-enter into the cell cycle and resume proliferation leading to recurrence. However, the molecular and cellular regulators underlying this transition remain poorly understood. To date, three mechanisms have been identified to trigger tumor dormancy including cellular, angiogenic, and immunologic dormancies. In addition, recent studies have suggested that DNA repair mechanisms may contribute to the survival of dormant cancer cells. In this article, we summarize the recent experimental and clinical evidence governing cancer dormancy. In addition, we will discuss the role of DNA repair mechanisms in promoting the survival of dormant cells. This information provides mechanistic insight to explain why recurrence occurs, and strategies that may enhance therapeutic approaches to prevent disease recurrence. 展开更多
关键词 QUIESCENCE HOMOLOGOUS recombination Non-homologous end joining Tumor DORMANCY dna repair
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Primer-Like Inhibitors for DNA Repair Enzymes of the AML-HL60 and WERI-1A/Y79 Malignant Cells
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作者 Sergei V. Stovbun Kirill V. Ermakov +2 位作者 Alexander A. Bukhvostov Alexander S. Vedenkin Dmitry A. Kuznetsov 《Advances in Enzyme Research》 2019年第3期27-44,共18页
A conventionally synthesized thio- and cyano-modified single-stranded poly(dNTP) sequences of different molecular sizes (20n - 200n) and the same lengths routine poly(dNTP) and poly(NTP) species were obtained through ... A conventionally synthesized thio- and cyano-modified single-stranded poly(dNTP) sequences of different molecular sizes (20n - 200n) and the same lengths routine poly(dNTP) and poly(NTP) species were obtained through the good services provided by the Russian Federal Bioorganic Products Group and by the ThermoFischer, Inc., and then tested for their impact on catalytic activities of β-like DNA polymerases from chromatin of HL-60, WERI-1A and Y-79 cells as well as for the affinity patterns in DNApolβ-poly(dNTP)/ (NTP) pairs, respectively. An essential link between the lengths of ultrashort (50n - 100n) single-stranded poly(dNTP) sequences of different structures and their inhibitory effects towards the cancer-specific DNA polymerases β has been found. A possible significance of this phenomenon for both DNA repair suppression in tumors and a consequent anti-cancer activity of the DNA repair related short poly(dNTP) fragments has been for the first time emphasized with a respect to their pharmacophore revealing potential. Thus, this work presents an experimental attempt to upgrade a contemporary attitude towards the DNA derived products applied for anti-cancer agenda, particularly, for acute myeloid leukemia and retinoblastoma cell DNA repair machinery breakdown. In this study, tumor specific DNA polymerases β were found of being the targets for attack promoted with the primer-like single-stranded DNA fragments followed by consequent cytostatic phenomena. A novel concept of the DNA related anti-cancer medicines is under discussion. 展开更多
关键词 Magnetic ISOTOPE Effects (MIE) dna repair dna POLYMERASES dna-Enzyme Binding
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STIMULATING EFFECT OF LOW DOSE ^(147)Pm ON DNA REPAIR IN SPERMIOGENIC STAGES
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作者 朱寿彭 王六一 《Nuclear Science and Techniques》 SCIE CAS CSCD 1995年第1期18-21,共4页
STIMULATINGEFFECTOFLOWDOSE^(147)PmONDNAREPAIRINSPERMIOGENICSTAGESSTIMULATINGEFFECTOFLOWDOSE^(147)PmONDNAREPAI... STIMULATINGEFFECTOFLOWDOSE^(147)PmONDNAREPAIRINSPERMIOGENICSTAGESSTIMULATINGEFFECTOFLOWDOSE^(147)PmONDNAREPAIRINSPERMIOGENICST... 展开更多
关键词 dna修复 低剂量147Pm 激励效应
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The Potential of Targeting DNA Repair Deficiency in Acute Myeloid Leukemia
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作者 Clare M. Crean Ken I. Mills Kienan I. Savage 《Journal of Cancer Therapy》 2017年第8期691-698,共8页
Acute myeloid leukemia (AML) is a clonal heterogeneous disease of the myeloid white blood cells. It is characterised by an accumulation of immature blast cells and a number of chromosomal and genetic mutations have be... Acute myeloid leukemia (AML) is a clonal heterogeneous disease of the myeloid white blood cells. It is characterised by an accumulation of immature blast cells and a number of chromosomal and genetic mutations have been identified. In both de novo and therapy-related AML, defective DNA repair mechanisms are responsible for some of these genetic abnormalities. Targeting the DNA repair mechanism has been shown to be successful against certain forms of solid tumors and may represent a novel therapeutic approach for AML. 展开更多
关键词 dna repair ACUTE MYELOID LEUKEMIA
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