A Novel ATM Antisense Transcript ATM-AS Positively Regulates ATM Expression in Normal and Breast Cancer Cells  被引量:2

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作  者:He CHENG Er-shao ZHANG Xiao SHI Ping-ping CAO Bei-jing PAN Xin-xin SI Yue LIU Nan YANG Ying CHU Xu-chun WANG Xiao HAN Zhi-hong ZHANG Yu-jie SUN 

机构地区:[1]Key Laboratory of Human Functional Genomics of Jiangsu Province,Nanjing Medical University,Nanjing 210000,China [2]Department of Pathology,the First Affiliated Hospital of Nanjing Medical University,Nanjing 210000,China [3]Key Laboratory of Cancer Biomarkers,Prevention and Treatment,Collaborative Innovation Center for Personalized Cancer Medicine,Nanjing Medical University,Nanjing 210000,China [4]Department of Cell Biology,Nanjing Medical University,Nanjing 210000,China

出  处:《Current Medical Science》2022年第4期681-691,共11页当代医学科学(英文)

基  金:supported by the National Natural Science Foundation of China(No.81802670 and No.82072580).

摘  要:Objective:The ataxia telangiectasia mutated(ATM)gene is a master regulator in cellular DNA damage response.The dysregulation of ATM expression is frequent in breast cancer,and is known to be involved in the carcinogenesis and prognosis of cancer.However,the underlying mechanism remains unclear.The bioinformatic analysis predicted a potential antisense transcript ATM-antisense(AS)from the opposite strand of the ATM gene.The purpose of this study was to identify ATM-AS and investigate the possible effect of ATM-AS on the ATM gene regulation.Methods:Single strand-specific RT-PCR was performed to verify the predicted antisense transcript ATM-AS within the ATM gene locus.qRT-PCR and Western blotting were used to detect the expression levels of ATM-AS and ATM in normal and breast cancer cell lines as well as in tissue samples.Luciferase reporter gene assays,biological mass spectrometry,ChIP-qPCR and RIP were used to explore the function of ATM-AS in regulating the ATM expression.Immunofluorescence and host-cell reactivation(HCR)assay were performed to evaluate the biological significance of ATM-AS in ATM-mediated DNA damage repair.Breast cancer tissue samples were used for evaluating the correlation of the ATM-AS level with the ATM expression as well as prognosis of the patients.Results:The ATM-AS significantly upregulated the ATM gene activity by recruiting KAT5 histone acetyltransferase to the gene promoter.The reduced ATM-AS level led to the abnormal downregulation of ATM expression,and impaired the ATM-mediated DNA damage repair in normal breast cells in vitro.The ATM-AS level was positively correlated with the ATM expression in the examined breast cancer tissue samples,and the patient prognosis.Conclusion:The present study demonstrated that ATM-AS,an antisense transcript located within the ATM gene body,is an essential positive regulator of ATM expression,and functions by mediating the binding of KAT5 to the ATM promoter.These findings uncover the novel mechanism underlying the dysregulation of the ATM gene in bre

关 键 词:antisense transcript ataxia telangiectasia mutated ataxia telangiectasia mutatedantisense breast cancer KAT5 

分 类 号:R737.9[医药卫生—肿瘤]

 

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