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Establishing the homologous recombination score threshold in metastatic prostate cancer patients to predict the efficacy of PARP inhibitors
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作者 Diwei Zhao Anqi Wang +8 位作者 Yuanwei Li Xinyang Cai Junliang Zhao Tianyou Zhang Yi Zhao Yu Dong Fangjian Zhou Yonghong Li Jun Wang 《Journal of the National Cancer Center》 2024年第3期280-287,共8页
Background:The homologous recombination deficiency(HRD)score serves as a promising biomarker to iden-tify patients who are eligible for treatment with PARP inhibitors(PARPi).Previous studies have suggested a 3-biomark... Background:The homologous recombination deficiency(HRD)score serves as a promising biomarker to iden-tify patients who are eligible for treatment with PARP inhibitors(PARPi).Previous studies have suggested a 3-biomarker Genomic Instability Score(GIS)threshold of≥42 as a valid biomarker to predict response to PARPi in patients with ovarian cancer and breast cancer.However,the GIS threshold for prostate cancer(PCa)is still lacking.Here,we conducted an exploratory analysis to investigate an appropriate HRD score threshold and to evaluate its ability to predict response to PARPi in PCa patients.Methods:A total of 181 patients with metastatic castration-resistant PCa were included in this study.Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair(HRR)genes and copy number variation(CNV)analysis.The HRD score was calculated based on over 50,000 single-nucleotide polymorphisms(SNP)distributed across the human genome,incorporating three SNP-based as-says:loss of heterozygosity,telomeric allelic imbalance,and large-scale state transition.The HRD score threshold was set at the last 5th percentile of the HRD scores in our cohort of known HRR-deficient tumors.The relation-ship between the HRD score and the efficacy in 16 patients of our cohort who received PARPi treatment were retrospectively analyzed.Results:Genomic testing was succeeded in 162 patients.In our cohort,61 patients(37.7%)had HRR mutations(HRRm).BRCA mutations occurred in 15 patients(9.3%).The median HRD score was 4(ranged from 0 to 57)in the total cohort,which is much lower than that in breast and ovarian cancers.Patients who harbored HRRm and BRCA or TP53 mutations had higher HRD scores.CNV occured more frequently in patients with HRRm.The last 5th percentile of HRD scores was 43 in the HRR-mutant cohort and consequently HRD high was defined as HRD scores≥43.In the 16 patients who received PARPi in our cohort,4 patients with a high HRD score achieved an objective response rate(ORR)of 100%while 12 patients with a low HRD score achieved an ORR of 8.3%.Progression-free survival(PFS)in HRD high patients was longer compared to HRD low patients,regardless of HRRm.Conclusions:A HRD score threshold of 43 was established and preliminarily validated to predict the efficacy of PARPi in this study.Future studies are needed to further verify this threshold. 展开更多
关键词 homologous recombination deficiency score THRESHOLD PARP inhibitors homologous recombination repair pathway MUTATION BRCA
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Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population:An integrated genomic and transcriptional analysis
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作者 Yifei Wang Yidan Ma +14 位作者 Lei He Jun Du Xiaoguang Li Peng Jiao Xiaonan Wu Xiaomao Xu Wei Zhou Li Yang Jing Di Changbin Zhu Liming Xu Tianlin Sun Lin Li Dongge Liu Zheng Wang 《Chinese Journal of Cancer Research》 SCIE CAS CSCD 2024年第3期282-297,共16页
Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not ... Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not been fully investigated.This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.Methods:A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled.HRD status was assessed using the AmoyDx Genomic Scar Score(GSS),with a score of≥50 considered HRD-positive.Genomic,transcriptomic,tumor microenvironmental characteristics and prognosis between HRD-positive and HRDnegative patients were analyzed.Results:Of the patients,25.1%(89/355)were HRD-positive.Compared to HRD-negative patients,HRDpositive patients had more somatic pathogenic homologous recombination repair(HRR)mutations,higher tumor mutation burden(TMB)(P<0.001),and fewer driver gene mutations(P<0.001).Furthermore,HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes,MET and MYC in epidermal growth factor receptor(EGFR)/anaplastic lymphoma kinase(ALK)mutant NSCLC,and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC.HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity.HRD-negative NSCLC showed activated signatures of major histocompatibility complex(MHC)-II,interferon(IFN)-γand effector memory CD8+T cells.HRD-positive patients had a worse prognosis and shorter progressionfree survival(PFS)to targeted therapy(first-and third-generation EGFR-TKIs)(P=0.042).Additionally,HRDpositive,EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.Conclusions:Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC.Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC.This study highlights potential actionable alterations in HRD-positive NSCLC,suggesting possible combinational therapeutic strategies for these patients. 展开更多
关键词 Non-small cell lung cancer homologous recombination deficiency genetic alterations transcriptional analysis tumor microenvironment PROGNOSIS
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Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients
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作者 Naveed Syed Ashish Vittalrao Chintakuntlawar +6 位作者 Deepti Vilasini Aisha Mohamed Al Salami Riad Al Hasan Imrana Afrooz Kanishka Uttam Chandani Ashok Uttam Chandani Aref Chehal 《World Journal of Clinical Oncology》 2024年第7期848-858,共11页
BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breas... BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients. 展开更多
关键词 homologous recombination repair BRCA1 BRCA2 homologous recombination deficiency Ovarian cancer Breast cancer Poly(ADP-ribose)polymerase inhibitors OLAPARIB DNA double-strand breaks
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Association between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancer 被引量:2
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作者 Yimeng Chen Xue Wang +8 位作者 Feng Du Jian Yue Yiran Si Xiaochen Zhao Lina Cui Bei Zhang Ting Bei Binghe Xu Peng Yuan 《Cancer Biology & Medicine》 SCIE CAS CSCD 2023年第2期155-168,共14页
Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatm... Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings. 展开更多
关键词 homologous recombination deficiency triple-negative breast cancer PLATINUM SURVIVAL BRCA
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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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miR-506: a regulator of chemo-sensitivity through suppression of the RAD51-homologous recombination axis 被引量:4
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作者 Guoyan Liu Fengxia Xue Wei Zhang 《Chinese Journal of Cancer》 SCIE CAS CSCD 2015年第11期485-487,共3页
Ovarian carcinoma is the most lethal gynecologic malignancy. Resistance to platinum is considered the major problem afecting prognosis. Our recent study established that micro RNA-506(mi R-506) expression was closely ... Ovarian carcinoma is the most lethal gynecologic malignancy. Resistance to platinum is considered the major problem afecting prognosis. Our recent study established that micro RNA-506(mi R-506) expression was closely associated with progression-free survival and overall survival in two independent patient cohorts totaling 598 epithelial ovarian cancer cases. Further functional study demonstrated that mi R-506 could augment the response to cisplatin and olaparib through targeting RAD51 and suppressing homologous recombination in a panel of ovarian cancer cell lines. Systemic delivery of mi R-506 in an orthotopic ovarian cancer mouse model signiicantly augmented the cisplatin response, thus recapitulating the clinical observation. Therefore, mi R-506 plays a functionally important role in homologous recombination and has important therapeutic value for sensitizing cancer cells to chemotherapy, especially in chemo-resistant patients with attenuated expression of mi R-506. 展开更多
关键词 MicroRNA-506 homologous recombination DRUG sensitivity Synthetic lethality RAD51
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The mutational pattern of homologous recombination(HR)-associated genes and its relevance to the immunotherapeutic response in gastric cancer 被引量:6
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作者 Yue Fan Haifeng Ying +7 位作者 Xueying Wu Huan Chen Ying Hu Henghui Zhang Lijia Wu Ying Yang Beibei Mao Lan Zheng 《Cancer Biology & Medicine》 SCIE CAS CSCD 2020年第4期1002-1013,共12页
Objective:Currently,there is an urgent need to identify immunotherapeutic biomarkers to increase the benefit of immune checkpoint inhibitors(ICIs)for patients with gastric cancer(GC).Homologous recombination deficienc... Objective:Currently,there is an urgent need to identify immunotherapeutic biomarkers to increase the benefit of immune checkpoint inhibitors(ICIs)for patients with gastric cancer(GC).Homologous recombination deficiency(HRD)can modify the tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic response.We aimed to analyze the mutational pattern of HR-associated genes in Chinese patients with GC and its relevance to the tumor immune profile and clinical immunotherapeutic response.Methods:A panel of 543 cancer-associated genes was used to analyze genomic profiles in a cohort comprising 484 Chinese patients with GC.Correlations between HR gene mutations and tumor immunity or clinical outcomes were identified via bioinformatic analysis using 2 GC genomic datasets(TCGA and MSK-IMPACT).Results:Fifty-one of the 484(10.54%)patients carried at least one somatic mutation in an HR gene;ATM(16/484,3.31%)was among the most frequently mutated HR genes in the Chinese cohort.Mutations in HR genes were associated with elevated tumor mutational burden,enhanced immune activity,and microsatellite instability status.In the MSK-IMPACT cohort comprising 49 patients with stomach adenocarcinoma or gastroesophageal junction adenocarcinoma treated with ICIs,patients with HR-mut GC(n=12)had significantly better overall survival than those with HR-wt GC(n=37)(log-rank test,P<0.05).Conclusions:Our data suggest that detection of somatic mutations in HR genes might aid in identifying patients who might benefit from immune checkpoint blockade therapy. 展开更多
关键词 Gastric cancer homologous recombination deficiency IMMUNOTHERAPY BIOMARKER
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Inhibition of KU70 and KU80 by CRISPR interference,not NgAgo interference,increases the efficiency of homologous recombination in pig fetal fibroblasts 被引量:2
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作者 LI Guo-ling QUAN Rong +10 位作者 WANG Hao-qiang RUAN Xiao-fang MO Jian-xin ZHONG Cui-li YANG Huaqiang LI Zi-cong GU Ting LIU De-wu WU Zhen-fang CAI Geng-yuan ZHANG Xian-wei 《Journal of Integrative Agriculture》 SCIE CAS CSCD 2019年第2期438-448,共11页
Non-homologous end-joining(NHEJ) is a predominant pathway for the repair of DNA double-strand breaks(DSB). It inhibits the efficiency of homologous recombination(HR) by competing for DSB targets. To improve the effici... Non-homologous end-joining(NHEJ) is a predominant pathway for the repair of DNA double-strand breaks(DSB). It inhibits the efficiency of homologous recombination(HR) by competing for DSB targets. To improve the efficiency of HR, multiple CRISPR interference(CRISPRi) and Natronobacterium gregoryi Argonaute(NgAgo) interference(NgAgoi) systems have been designed for the knockdown of NHEJ key molecules, KU70, KU80, polynucleotide kinase/phosphatase(PNKP), DNA ligase IV(LIG4), and NHEJ1. Suppression of KU70 and KU80 by CRISPRi dramatically promoted(P<0.05) the efficiency of HR to 1.85-and 1.58-fold, respectively, whereas knockdown of PNKP, LIG4, and NHEJ1 repair factors did not significantly increase(P>0.05) HR efficiency. Interestingly, although the NgAgoi system significantly suppressed(P<0.05) KU70, KU80, PNKP, LIG4, and NHEJ1 expression, it did not improve(P>0.05) HR efficiency in primary fetal fibroblasts. Our result showed that both NgAgo and catalytically inactive Cas9(dCas9) could interfere with the expression of target genes, but the downstream factors appear to be more active following CRISPR-mediated interference than that of NgAgo. 展开更多
关键词 homologous recombination non-homologous end-joining CRISPRi NgAgoi KU70 KU80
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Construction of recombinant industrial Saccharomyces cerevisiae strain with bglS gene insertion into PEP4 locus by homologous recombination 被引量:6
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作者 Qiang ZHANG Qi-he CHEN Ming-liang FU Jin-ling WANG Hong-bo ZHANG Guo-qing HE 《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》 SCIE CAS CSCD 2008年第7期527-535,共9页
The bglS gene encoding endo-1,3-1,4-β-glucanase from Bacillus subtil& was cloned and sequenced in this study. The bglS expression cassette, including PGK1 promoter, bglS gene fused to the signal sequence of the yeas... The bglS gene encoding endo-1,3-1,4-β-glucanase from Bacillus subtil& was cloned and sequenced in this study. The bglS expression cassette, including PGK1 promoter, bglS gene fused to the signal sequence of the yeast mating pheromone a-factor (MFals), and ADH1 terminator with G418-resistance as the selected marker, was constructed. Then one of the PEP4 allele of Saccharomyces cerevisiae WZ65 strain was replaced by bglS expression cassette using chromosomal integration of polymerase chain reaction (PCR)-mediated homologous recombination, and the bglS gene was expressed simultaneously. The recombinant strain S. cerevisiae (SC-βG) was preliminarily screened by the clearing hydrolysis zone formed after the barley β-glucan was hydrolyzed in the plate and no proteinase A (PrA) activity was measured in fermenting liquor. The results of PCR analysis of genome DNA showed that one of the PEP4 allele had been replaced and bglS gene had been inserted into the locus of PEP4 gene in recombinant strains. Different endo-1,3-1,4-β-glucanase assay methods showed that the recombinant strain SC-βG had high endo-1,3-1,4-β-glucanase expression level with the maximum of 69.3 U/(h·ml) after 60 h of incubation. Meanwhile, the Congo Red method was suitable for the determination of endo-1,3-1,4-β-glucanase activity during the actual brewing process. The current research implies that the constructed yeast strain could be utilized to improve the industrial brewing property of beer. 展开更多
关键词 Endo-1 3-1 4-β-glucanase (bglS) Gene replacement homologous recombination Bacillus subtilis PEP4 gene Saccharomyces cerevisiae
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BLM helicase inhibition synergizes with PARP inhibition to improve the radiosensitivity of olaparib resistant non-small cell lung cancer cells by inhibiting homologous recombination repair 被引量:2
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作者 Yangyang Kong Chang Xu +11 位作者 Xiaohui Sun Hao Sun Xiaotong Zhao Ningning He Kaihua Ji Qin Wang Liqing Du Jinhan Wang Manman Zhang Yang Liu Yan Wang Qiang Liu 《Cancer Biology & Medicine》 SCIE CAS CSCD 2022年第8期1150-1171,共22页
Objective:We aimed to investigate the radiosensitizing efficacy of the poly-ADP-ribose polymerase(PARP)inhibitor,olaparib,and the Bloom syndrome protein(BLM)helicase inhibitor,ML216,in non-small cell lung cancer(NSCLC... Objective:We aimed to investigate the radiosensitizing efficacy of the poly-ADP-ribose polymerase(PARP)inhibitor,olaparib,and the Bloom syndrome protein(BLM)helicase inhibitor,ML216,in non-small cell lung cancer(NSCLC)cells.Methods:Radiosensitization of NSCLC cells was assessed by colony formation and tumor growth assays.Mechanistically,the effects of ML216,olaparib,and radiation on cell and tumor proliferation,DNA damage,cell cycle,apoptosis,homologous recombination(HR)repair,and non-homologous end joining(NHEJ)repair activity were determined.Results:Both olaparib and ML216 enhanced the radiosensitivities of olaparib-sensitive H460 and H1299 cells,which was seen as decreased surviving fractions and Rad51 foci,increased total DNA damage,andγH2AX and 53BP1 foci(P<0.05).The expressions of HR repair proteins were remarkably decreased in olaparib-treated H460 and H1299 cells after irradiation(P<0.05),while olaparib combined with ML216 exerted a synergistic radiosensitization effect on olaparib-resistant A549 cells.In addition to increases of double strand break(DSB)damage and decreases of Rad51 foci,olaparib combined with ML216 also increased pDNA-PKcs(S2056)foci,abrogated G2 cell cycle arrest,and induced apoptosis in A549 lung cancer after irradiation in vitro and in vivo(P<0.05).Moreover,Western blot showed that olaparib combined with ML216 and irradiation inhibited HR repair,promoted NHEJ repair,and inactivated cell cycle checkpoint signals both in vitro and in vivo(P<0.05).Conclusions:Taken together,these results showed the efficacy of PARP and BLM helicase inhibitors for radiosensitizing NSCLC cells,and supported the model that BLM inhibition sensitizes cells to PARP inhibitor-mediated radiosensitization,as well as providing the basis for the potential clinical development of this combination for tumors intrinsically resistant to PARP inhibitors and radiotherapy. 展开更多
关键词 NSCLC PARP BLM RADIOSENSITIZATION homologous recombination repair
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Maternal gene Ooep may participate in homologous recombination-mediated DNA double-strand break repair in mouse oocytes 被引量:1
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作者 Da-Jian He Lin Wang +5 位作者 Zhi-Bi Zhang Kun Guo Jing-Zheng Li Xie-Chao He Qing-Hua Cui Ping Zheng 《Zoological Research》 SCIE CAS CSCD 2018年第6期387-395,共9页
DNA damage in oocytes can cause infertility and birth defects. DNA double-strand breaks (DSBs) are highly deleterious and can substantially impair genome integrity. Homologous recombination (HR)-mediated DNA DSB r... DNA damage in oocytes can cause infertility and birth defects. DNA double-strand breaks (DSBs) are highly deleterious and can substantially impair genome integrity. Homologous recombination (HR)-mediated DNA DSB repair plays dominant roles in safeguarding oocyte quantity and quality. However, little is known regarding the key players of the HR repair pathway in oocytes. Here, we identified oocyte-specific gene Ooep as a novel key component of the HR repair pathway in mouse oocytes. OOEP was required for efficient ataxia telangiectasia mutated (ATM) kinase activation and Rad51 recombinase (RAD51) focal accumulation at DNA DSBs. Ooep null oocytes were defective in DNA DSB repair and prone to apoptosis upon exogenous DNA damage insults. Moreover, Ooep null oocytes exhibited delayed meiotic maturation. Therefore, OOEP played roles in preserving oocyte quantity and quality by maintaining genome stability. Ooep expression decreased with the advance of maternal age, suggesting its involvement in maternal aging. 展开更多
关键词 Ooep homologous recombination DNA double-strand break repair ATM RAD51
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Phylogeny and Homologous Recombination Occurring in Classical Swine Fever Viruses
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作者 Jiang Qing-yun Gao Yu +4 位作者 Li Wei-qun Ding Fan Juergen Richt Ren Yu-dong Li Guang-xing 《Journal of Northeast Agricultural University(English Edition)》 CAS 2019年第3期57-65,共9页
Classical swine fever virus(CSFV) is the causative agent of classical swine fever, a highly contagious disease of pigs. But there is little information on the recombination in natural populations of CSFVs. Therefore, ... Classical swine fever virus(CSFV) is the causative agent of classical swine fever, a highly contagious disease of pigs. But there is little information on the recombination in natural populations of CSFVs. Therefore, a phylogenetic analysis of 62 fulllength genome CSFV strains, isolated from all over the world, was performed to detect potential recombination events, with the recombinant sequences being analyzed with the SimPlot and RDP programs. The results identified a mosaic virus, Chinese CSFV HCLV(2)(AF091507.1), which is the one naturally emerged recombinant CSFV with two recombination breakpoints at 2 484 and 2 900 bp of the genome alignment. Its two putative parental-like strains were CSFV Shimen(AF092448.2) and CSFV strain C/HVRI(AY805221.1). This work demonstrated that homologous recombination did occur in natural CSFV populations. It had significant implications for understanding the molecular epidemiology of CSFV, and revealed that recombination was an important factor for high genetic diversities of CSFV. 展开更多
关键词 CLASSICAL SWINE FEVER virus homologous recombination PHYLOGENY genetic diversity
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Phylogeny and Homologous Recombination in Japanese Encephalitis Viruses
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作者 Li Xiao-xue Cong Ying-ying +4 位作者 Wang Xin Ren Yu-dong Ren Xiao-feng Lu Ai-guo Li Guang-xing 《Journal of Northeast Agricultural University(English Edition)》 CAS 2015年第1期40-49,共10页
Japanese encephalitis virus(JEV) is a significant causative agent of arthropod-borne encephalitis and what is less clear that the factors cause the virus wide spread. The objective was to confirm whether the homolog... Japanese encephalitis virus(JEV) is a significant causative agent of arthropod-borne encephalitis and what is less clear that the factors cause the virus wide spread. The objective was to confirm whether the homologous recombination imposed on JEV. The phylogenetic and homologous recombination analyses were performed based on 163 complete JEV genomes which were recently isolated. They were still separated into five genotypes(GI-GV) and the most of recently isolated JEVs were GI rather than GIII in Asian areas including China's Mainland. Two recombinant events were identified in JEV and the evidence of the recombination was observed between China and Japan isolates that partitioned into two distinct subclades, but still the same genotype(GIII). Our data further suggested that most of the nucleotides in JEV genome were under negative selection; however, changes within codon 2 316(amino acid NS4b-44) showed an evidence of the positive selection. 展开更多
关键词 Japanese encephalitis virus PHYLOGENY homologous recombination
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Caseinolytic mitochondrial matrix peptidase X is essential for homologous chromosome synapsis and recombination during meiosis of male mouse germ cells
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作者 Hai-Wei Feng Yu Zhao +2 位作者 Yan-Ling Gao Dong-Teng Liu Li-Jun Huo 《Asian Journal of Andrology》 SCIE CAS CSCD 2024年第2期165-174,共10页
Meiosis is the process of producing haploid gametes through a series of complex chromosomal events and the coordinated action of various proteins.The mitochondrial protease complex(ClpXP),which consists of caseinolyti... Meiosis is the process of producing haploid gametes through a series of complex chromosomal events and the coordinated action of various proteins.The mitochondrial protease complex(ClpXP),which consists of caseinolytic mitochondrial matrix peptidase X(ClpX)and caseinolytic protease P(ClpP)and mediates the degradation of misfolded,damaged,and oxidized proteins,is essential for maintaining mitochondrial homeostasis.ClpXP has been implicated in meiosis regulation,but its precise role is currently unknown.In this study,we engineered an inducible male germ cell-specific knockout caseinolytic mitochondrial matrix peptidase X(Clpx^(cKO))mouse model to investigate the function of ClpX in meiosis.We found that disrupting Clpx in male mice induced germ cell apoptosis and led to an absence of sperm in the epididymis.Specifically,it caused asynapsis of homologous chromosomes and impaired meiotic recombination,resulting in meiotic arrest in the zygotene-to-pachytene transition phase.The loss of ClpX compromised the double-strand break(DSB)repair machinery by markedly reducing the recruitment of DNA repair protein RAD51 homolog 1(RAD51)to DSB sites.This dysfunction may be due to an insufficient supply of energy from the aberrant mitochondria in Clpx^(cKO) spermatocytes,as discerned by electron microscopy.Furthermore,ubiquitination signals on chromosomes and the expression of oxidative phosphorylation subunits were both significantly attenuated in Clpx^(cKO) spermatocytes.Taken together,we propose that ClpX is essential for maintaining mitochondrial protein homeostasis and ensuring homologous chromosome pairing,synapsis,and recombination in spermatocytes during meiotic prophase I. 展开更多
关键词 ClpX homologous chromosome MEIOSIS MITOCHONDRIAL recombination SYNAPSIS
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Facilitating stable gene integration expression and copy number amplification in Bacillus subtilis through a reversible homologous recombination switch
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作者 Haoyu Guo Rongzhen Tian +6 位作者 Yaokang Wu Xueqin Lv Jianghua Li Long Liu Guocheng Du Jian Chen Yanfeng Liu 《Synthetic and Systems Biotechnology》 SCIE CSCD 2024年第3期577-585,共9页
Strengthening the expression level of integrated genes on the genome is crucial for consistently expressing key enzymes in microbial cell factories for efficient bioproduction in synthetic biology.In comparison to pla... Strengthening the expression level of integrated genes on the genome is crucial for consistently expressing key enzymes in microbial cell factories for efficient bioproduction in synthetic biology.In comparison to plasmid-based multi-copy expression,the utilization of chromosomal multi-copy genes offers increased stability of expression level,diminishes the metabolic burden on host cells,and enhances overall genetic stability.In this study,we developed the“BacAmp”,a stabilized gene integration expression and copy number amplification system for high-level expression in Bacillus subtilis,which was achieved by employing a combination of repressor and non-natural amino acids(ncAA)-dependent expression system to create a reversible switch to control the key gene recA for homologous recombination.When the reversible switch is turned on,genome editing and gene amplification can be achieved.Subsequently,the reversible switch was turned off therefore stabilizing the gene copy number.The stabilized gene amplification system marked by green fluorescent protein,achieved a 3-fold increase in gene expression by gene amplification and maintained the average gene copy number at 10 after 110 generations.When we implemented the gene amplification system for the regulation of N-acetylneuraminic acid(NeuAc)synthesis,the copy number of the critical gene increased to an average of 7.7,which yielded a 1.3-fold NeuAc titer.Our research provides a new avenue for gene expression in synthetic biology and can be applied in metabolic engineering in B.subtilis. 展开更多
关键词 Bacillus subtilis Stabilized gene amplification system homologous recombination RECA
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ILF3 safeguards telomeres from aberrant homologous recombination as a telomeric R-loop reader
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作者 Chuanle Wang Yan Huang +7 位作者 Yue Yang Ruofei Li Yingying Li Hongxin Qiu Jiali Wu Guang Shi Wenbin Ma Zhou Songyang 《Protein & Cell》 SCIE CSCD 2024年第7期493-511,共19页
Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability.The telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stran... Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability.The telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop.In tumor cells,R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres(ALT)pathway.Dysregulated R-loops can cause stalled replication forks and telomere instability.However,how R-loops are recognized and regulated,particularly at telomeres,is not well understood.We discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination.Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses.In addition,ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway.Using the proximity-dependent biotin identification(BioID)technology,we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases,including DHX9.Importantly,ILF3 may aid in the resolution of telomeric R-loops through its interaction with DHX9.Our findings suggest that ILF3 may function as a reader of telomeric R-loops,helping to prevent abnormal homologous recombination and maintain telomere homeostasis. 展开更多
关键词 ILF3 RNA:DNA hybrids telomeric R-loops homologous recombination telomeric DNA damage responses
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TP53-specific mutations serve as a potential biomarker for homologous recombination deficiency in breast cancer:a clinical next-generation sequencing study
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作者 Yongsheng Huang Shuwei Ren +7 位作者 Linxiaoxiao Ding Yuanling jiang Jiahuan Luo Jinghua Huang Xinke Yin Jianli Zhao Sha Fu Jianwei Liao 《Precision Clinical Medicine》 2024年第2期122-131,共10页
Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast cancer.However,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear... Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast cancer.However,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear.Methods:Clinical next-generation sequencing(NGS)of both tumor and paired blood DNA from 119 breast cancer patients(BRCA-119 cohort)was performed with a 520-gene panel.Mutations,tumor mutation burden(TMB),and genomic HRD scores were assessed from NGS data.NGS data from 47 breast cancer patients in the HRD test cohort were analyzed for further verification.Results:All TP53 pathogenic mutations in patients had somatic origin,which was associated with the protein expression of estrogen receptor and progestogen receptor.Compared to patients without TP53 pathologic mutations,patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations.The frequency of TP53 pathologic mutation was higher in the HRDhigh group(HRD score≥42)relative to that in the HRD-low group(HRD score<42).TP53 has different mutational characteristics between the HRD-low and HRD-high groups.TP53-specific mutation subgroups had diverse genomic features and TMB.Notably,TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve(AUC)of 0.61.TP53-specific mutations,namely HRD-low mutation,HRD-high mutation,and HRD common mutation,predicted the HRD status of breast cancer patients with AUC values of 0.32,0.72,and 0.58,respectively.Interestingly,TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values(0.80)in predicting HRD status.Conclusions:TP53-specific mutation combinations predict the HRD status of patients,indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase(PARP)inhibitors in breast cancer patients. 展开更多
关键词 next-generation sequencing homologous recombination deficiency TP53 breast cancer
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Role of homologous recombination/recombineering on human adenovirus genome engineering:Not the only but the most competent solution
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作者 Lisa-Marie Dawson Montaha Alshawabkeh +3 位作者 Katrin Schröer Fatima Arakrak Anja Ehrhardt Wenli Zhang 《Engineering Microbiology》 2024年第1期90-107,共18页
Adenoviruses typically cause mild illnesses,but severe diseases may occur primarily in immunodeficient individuals,particularly children.Recently,adenoviruses have garnered significant interest as a versatile tool in ... Adenoviruses typically cause mild illnesses,but severe diseases may occur primarily in immunodeficient individuals,particularly children.Recently,adenoviruses have garnered significant interest as a versatile tool in gene therapy,tumor treatment,and vaccine vector development.Over the past two decades,the advent of recombineering,a method based on homologous recombination,has notably enhanced the utility of adenoviral vectors in therapeutic applications.This review summarizes recent advancements in the use of human adenoviral vectors in medicine and discusses the pivotal role of recombineering in the development of these vectors.Additionally,it highlights the current achievements and potential future impact of therapeutic adenoviral vectors. 展开更多
关键词 Adenoviral vector Gene therapy homologous recombination Oncolytic virus Vaccine vector
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Red/ET同源重组介导的基因克隆载体pBACS的构建、鉴定与应用
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作者 侯少阳 李岚芳 +5 位作者 杜丽霞 孙林慧 李典 禚惠荣 姜莉莉 张大虎 《沈阳药科大学学报》 CAS CSCD 2024年第5期590-597,共8页
目的通过Red/ET同源重组技术构建pBACS基因克隆及测序质粒载体。方法以质粒pBAC2015、pET28a为模板设计四对引物,PCR扩增得到四段彼此间有50 bp同源区域的基因片段,分别命名为bac-sop、bac-ori、bac-kan和bac-T7。利用Red/ET同源重组技... 目的通过Red/ET同源重组技术构建pBACS基因克隆及测序质粒载体。方法以质粒pBAC2015、pET28a为模板设计四对引物,PCR扩增得到四段彼此间有50 bp同源区域的基因片段,分别命名为bac-sop、bac-ori、bac-kan和bac-T7。利用Red/ET同源重组技术,将四段基因片段电转至E.coli GB05-dir感受态中进行线线重组。经酶切、测序验证阳性克隆质粒。此外,对重组质粒pBACS进行稳定性鉴定;利用pBACS分别进行细菌16S rDNA和真菌ITS基因克隆和基因测序。结果酶切和测序的验证结果显示,质粒的大小、元件方向及序列正确;pBACS具有较强的稳定性,适用于作为基因工程的克隆载体;可高效用于细菌16S rDNA和真菌ITS序列的克隆,阳性率为100%。结论成功利用Red/ET技术构建克隆载体pBACS,质粒载体具有稳定性强、重组效率高的特点,在基因克隆和基因测序等方面具有良好的应用潜力。 展开更多
关键词 pBACS 克隆 red/ET技术 同源重组
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A method to synthesize cDNA constructs by homology based recombination cloning
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作者 Neetu Verma Pradeep Kumar Burma 《American Journal of Molecular Biology》 2014年第1期16-19,共4页
We introduce a homology-based recombination approach for generating a cDNA construct. This method depends on amplifying several exon fragments and their fusions by the homology-based recombination. This method provide... We introduce a homology-based recombination approach for generating a cDNA construct. This method depends on amplifying several exon fragments and their fusions by the homology-based recombination. This method provides a way to generate the cDNA sequence of any gene without any need for its mRNA. The paper describes the strategy by assembling cDNA of the MYB1 and MYB2 genes of Arabidopsis thaliana. 展开更多
关键词 homologY BASED recombination CLONING CDNA Assembly
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