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dna polymerase delta interacting protein 3 facilitates the activation and maintenance of dna damage checkpoint in response to replication stress

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Animal Models and Experimental Medicine 2022年第5期5卷 461-469页

作者： Sufang Zhang Ernest Y.C.Lee Marietta Y.W.T.Lee Dong Zhang Department of Biochemistry and Molecular Biology New York Medical CollegeNew YorkUSA Department of Biomedical Sciences College of Osteopathic MedicineNew York Institute of TechnologyNew YorkUSA

Background:Replication stress response is crucial for the maintenance of a stable ge-nome.POLDIP3(dna polymerase delta interacting protein 3)was initially identified as one of the dna polymeraseδ(Polδ)interacting proteins almost 20 years ago.Using a variety of in vitro biochemical assays,we previously established that POLDIP3 is a key regulator of the enzymatic activity of Polδ.However,the in vivo function of POLDIP3 in dna replication and dna damage response has been elusive.Methods:We first generated POLDIP3 knockout(KO)cells using the CRISPR/Cas9 technology.We then investigated its biological functions in vivo using a variety of biochemical and cell biology assays.Results:We showed that although the POLDIP3-KO cells manifest no pronounced defect in global dna synthesis under nonstress conditions,they are sensitive to a va-riety of replication fork blockers.Intriguingly,we found that POLDIP3 plays a crucial role in the activation and maintenance of the dna damage checkpoint in response to exogenous as well as endogenous replication stress.Conclusion:Our results indicate that when the dna replication fork is blocked,POLDIP3 can be recruited to the stalled replication fork and functions to bridge the early dna damage checkpoint response and the later replication fork repair/restart.

关键词： dna damage checkpoint dna polymerase delta POLDIP3 replication stress

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Hsp90-associated dna replication checkpoint protein and proteasome-subunit components are involved in the age-related macular degeneration

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Chinese Medical Journal 2021年第19期134卷 2322-2332页

作者： Chen Xing Xiao-Feng Liu Chun-Feng Zhang Liu Yang Department of Ophthalmology Peking University First HospitalBeijing 100034China Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education) Hepatopancreatobiliary Surgery Department IPeking University Cancer Hospital&InstituteBeijing 100142China Department of Medical Genetics School of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China

Background:Age-related macular degeneration(AMD)is the leading cause of vision loss worldwide.However,the mechanisms involved in the development and progression of AMD are poorly delineated.We aimed to explore the critical genes involved in the progression of AMD.Methods:The differentially expressed genes(DEGs)in AMD retinal pigment epithelial(RPE)/choroid tissues were identified using the microarray datasets GSE99248 and GSE125564,which were downloaded from the gene expression omnibus database.The overlapping DEGs from the two datasets were screened to identify DEG-related biological pathways using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.The hub genes were identified from these DEGs through protein-protein interaction network analyses.The expression levels of hub genes were evaluated by quantitative real-time polymerase chain reaction following the induction of senescence in ARPE-19 with FK866.Following the identification of AMD-related key genes,the potential small molecule compounds targeting the key genes were predicted by PharmacoDB.Finally,a microRNA-gene interaction network was constructed.Results:Microarray analyses identified 174 DEGs in the AMD RPE compared to the healthy RPE samples.These DEGs were primarily enriched in the pathways involved in the regulation of dna replication,cell cycle,and proteasome-mediated protein polyubiquitination.Among the top ten hub genes,HSP90AA1,CHEK1,PSMA4,PSMD4,and PSMD8 were upregulated in the senescent ARPE-19 cells.Additionally,the drugs targeting HSP90AA1,CHEK1,and PSMA4 were identified.We hypothesize that Hsa-miR-16-5p might target four out of the five key DEGs in the AMD RPE.Conclusions:Based on our findings,HSP90AA1 is likely to be a central gene controlling the dna replication and proteasome-mediated polyubiquitination during the RPE senescence observed in the progression of AMD.Targeting HSP90AA1,CHEK1,PSMA4,PSMD4,and/or PSMD8 genes through specific miRNAs or small molecules might potentially alleviate the progression of AMD

关键词： Age-related macular degeneration Retinal pigment epithelium Cell senescence HSP90AA1 dna damage checkpoint Proteasomal subunit components

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The expression of dna damage checkpoint proteins and prognostic implication in metastatic brain tumors

The expression of DNA damage checkpoint proteins and prognos...

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中国抗癌协会神经肿瘤专业委员会第八届学术会议

作者： Do-Hyun Nam Ho Jun Seol Hae Yong Yoo Juyoun Jin Kyeung Min Joo Jung-II Lee Department of Neurosurgery Samsung Biomedical Research Instituteand Cancer Stem Cell Research CenterSamsung Medical CenterSungkyunkwan University School of Medicine

Resistance to radiation is a possible cause of recurrence or treatment failure in brain metastasis.The expression of the dna damage checkpoint pathway components was investigated in cell lines and metastatic brain tumor（MBT） tissues.The association between the expression levels and survival outcome were evaluated to find out possible therapeutic targets in brain metastasis.Radiosensitivity of human non-small cell lung cancer cell lines was determined by checking their viability after treatment with varying doses of ionizing radiation（IR）.The expression of dna checkpoint proteins were analyzed by Western blots and immunohistochemistry.On the basis of the clinical data for the MBT patients,the association between the expression of the components and patients’ survival was investigated.The expression levels of TopBP1 and Chk1 protein were higher in radioresistant lung cancer cell line compared to radiosensitive cell lines.The activity of Chk1 in response to IR was also higher in radioresistant cell lines than in radiosensitive cell lines.We assessed radiation survival of lung cancer cell lines after treating them with Chk1 inhibitor,AZD7762.AZD7762 significantly sensitized both radioresistant and radiosensitive cells to IR.We also observed a strong inverse relationship between progression-free survival（PFS） and expression level of phosphorylated Chk1（P-Chk1） and TopBP1.The association between the PFS and the expression of TopBP1 and P-Chk1 was observed for the first time.Although further investigation for understanding the role of these proteins are necessary,these two dna damage checkpoints proteins can be promising targets for enhancing therapeutic potentials in the MBTs.

关键词： dna damage checkpoint metastatic brain tumor P-Chk1 radioresistance TopBP1

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