{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T19:48:23Z","timestamp":1770493703361,"version":"3.49.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T00:00:00Z","timestamp":1656979200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T00:00:00Z","timestamp":1656979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["CURR MED SCI"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Objective<\/jats:title>\n                <jats:p>The ataxia telangiectasia mutated (<jats:italic>ATM<\/jats:italic>) gene is a master regulator in cellular DNA damage response. The dysregulation of <jats:italic>ATM<\/jats:italic> 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 <jats:italic>ATM<\/jats:italic> gene. The purpose of this study was to identify ATM-AS and investigate the possible effect of ATM-AS on the <jats:italic>ATM<\/jats:italic> gene regulation.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Single strand-specific RT-PCR was performed to verify the predicted antisense transcript ATM-AS within the <jats:italic>ATM<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>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 <jats:italic>in vitro.<\/jats:italic> The ATM-AS level was positively correlated with the ATM expression in the examined breast cancer tissue samples, and the patient prognosis.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The present study demonstrated that ATM-AS, an antisense transcript located within the <jats:italic>ATM<\/jats:italic> gene body, is an essential positive regulator of ATM expression, and functions by mediating the binding of KAT5 to the <jats:italic>ATM<\/jats:italic> promoter. These findings uncover the novel mechanism underlying the dysregulation of the <jats:italic>ATM<\/jats:italic> gene in breast cancer, and enrich our understanding of how an antisense transcript regulates its host gene.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s11596-022-2585-5","type":"journal-article","created":{"date-parts":[[2022,7,5]],"date-time":"2022-07-05T04:05:36Z","timestamp":1656993936000},"page":"681-691","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A Novel ATM Antisense Transcript ATM-AS Positively Regulates ATM Expression in Normal and Breast Cancer Cells"],"prefix":"10.1007","volume":"42","author":[{"given":"He","family":"Cheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Er-shao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping-ping","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bei-jing","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin-xin","family":"Si","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Chu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu-chun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi-hong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-jie","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,7,5]]},"reference":[{"issue":"3","key":"2585_CR1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021,71(3):209\u2013249","journal-title":"CA Cancer J Clin"},{"issue":"10074","key":"2585_CR2","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1016\/S0140-6736(16)31891-8","volume":"389","author":"N Harbeck","year":"2017","unstructured":"Harbeck N, Gnant M. Breast cancer. Lancet, 2017,389(10074):1134\u20131150","journal-title":"Lancet"},{"issue":"4","key":"2585_CR3","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.molcel.2015.10.040","volume":"60","author":"MJ O\u2019Connor","year":"2015","unstructured":"O\u2019Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell, 2015,60(4):547\u2013560","journal-title":"Mol Cell"},{"issue":"2","key":"2585_CR4","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.radonc.2005.06.026","volume":"76","author":"O Zgheib","year":"2005","unstructured":"Zgheib O, Huyen Y, DiTullio RA, Jr., et al. ATM signaling and 53BP1. Radiother Oncol, 2005,76(2):119\u2013122","journal-title":"Radiother Oncol"},{"key":"2585_CR5","doi-asserted-by":"publisher","first-page":"6886","DOI":"10.1038\/ncomms7886","volume":"6","author":"V Stagni","year":"2015","unstructured":"Stagni V, Manni I, Oropallo V, et al. ATM kinase sustains HER2 tumorigenicity in breast cancer. Nat Commun, 2015,6:6886","journal-title":"Nat Commun"},{"issue":"4","key":"2585_CR6","first-page":"849","volume":"13","author":"PG Rio","year":"1998","unstructured":"Rio PG, Pernin D, Bay JO, et al. Loss of heterozygosity of BRCA1, BRCA2 and ATM genes in sporadic invasive ductal breast carcinoma. Int J Oncol, 1998,13(4):849\u2013853","journal-title":"Int J Oncol"},{"issue":"5","key":"2585_CR7","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1002\/gepi.21971","volume":"40","author":"M Marabelli","year":"2016","unstructured":"Marabelli M, Cheng SC, Parmigiani G. Penetrance of ATM Gene Mutations in Breast Cancer: A Meta-Analysis of Different Measures of Risk. Genet Epidemiol, 2016,40(5):425\u2013431","journal-title":"Genet Epidemiol"},{"issue":"9","key":"2585_CR8","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.1002\/cncr.22592","volume":"109","author":"C Ye","year":"2007","unstructured":"Ye C, Cai Q, Dai Q, et al. Expression patterns of the ATM gene in mammary tissues and their associations with breast cancer survival. Cancer, 2007,109(9):1729\u20131735","journal-title":"Cancer"},{"issue":"4","key":"2585_CR9","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1046\/j.1365-2559.2003.01713.x","volume":"43","author":"S Angele","year":"2003","unstructured":"Angele S, Treilleux I, Bremond A, et al. Altered expression of DNA double-strand break detection and repair proteins in breast carcinomas. Histopathology, 2003,43(4):347\u2013353","journal-title":"Histopathology"},{"issue":"5","key":"2585_CR10","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1136\/mp.52.5.252","volume":"52","author":"R Kairouz","year":"1999","unstructured":"Kairouz R, Clarke RA, Marr PJ, et al. ATM protein synthesis patterns in sporadic breast cancer. Mol Pathol, 1999,52(5):252\u2013256","journal-title":"Mol Pathol"},{"issue":"52","key":"2585_CR11","doi-asserted-by":"publisher","first-page":"85798","DOI":"10.18632\/oncotarget.12622","volume":"7","author":"X Feng","year":"2016","unstructured":"Feng X, Li H, Kornaga EN, et al. Low Ki67\/high ATM protein expression in malignant tumors predicts favorable prognosis in a retrospective study of early stage hormone receptor positive breast cancer. Oncotarget, 2016,7(52):85798\u201385812","journal-title":"Oncotarget"},{"key":"2585_CR12","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s13058-015-0575-2","volume":"17","author":"X Feng","year":"2015","unstructured":"Feng X, Li H, Dean M, et al. Low ATM protein expression in malignant tumor as well as cancer-associated stroma are independent prognostic factors in a retrospective study of early-stage hormone-negative breast cancer. Breast Cancer Res, 2015,17:65","journal-title":"Breast Cancer Res"},{"issue":"4","key":"2585_CR13","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1016\/j.molcel.2009.01.028","volume":"33","author":"S Mahmoudi","year":"2009","unstructured":"Mahmoudi S, Henriksson S, Corcoran M, et al. Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage. Mol Cell, 2009, 33(4):462\u2013471","journal-title":"Mol Cell"},{"issue":"1","key":"2585_CR14","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.neuron.2016.11.033","volume":"93","author":"C d\u2019Ydewalle","year":"2017","unstructured":"d\u2019Ydewalle C, Ramos DM, Pyles NJ, et al. The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy. Neuron, 2017,93(1):66\u201379","journal-title":"Neuron"},{"issue":"37","key":"2585_CR15","doi-asserted-by":"publisher","first-page":"4927","DOI":"10.1038\/onc.2016.25","volume":"35","author":"B Huang","year":"2016","unstructured":"Huang B, Song JH, Cheng Y, et al. Long non-coding antisense RNA KRT7-AS is activated in gastric cancers and supports cancer cell progression by increasing KRT7 expression. Oncogene, 2016,35(37):4927\u20134936","journal-title":"Oncogene"},{"issue":"9","key":"2585_CR16","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nrm2738","volume":"10","author":"MA Faghihi","year":"2009","unstructured":"Faghihi MA, Wahlestedt C. Regulatory roles of natural antisense transcripts. Nat Rev Mol Cell Biol, 2009,10(9):637\u2013643","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"12","key":"2585_CR17","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/nrg3594","volume":"14","author":"V Pelechano","year":"2013","unstructured":"Pelechano V, Steinmetz LM. Gene regulation by antisense transcription. Nat Rev Genet, 2013,14(12):880\u2013893","journal-title":"Nat Rev Genet"},{"issue":"5909","key":"2585_CR18","doi-asserted-by":"publisher","first-page":"1855","DOI":"10.1126\/science.1163853","volume":"322","author":"Y He","year":"2008","unstructured":"He Y, Vogelstein B, Velculescu VE, et al. The antisense transcriptomes of human cells. Science, 2008,322(5909):1855\u20131857","journal-title":"Science"},{"issue":"2","key":"2585_CR19","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/ng1157","volume":"34","author":"C Tufarelli","year":"2003","unstructured":"Tufarelli C, Stanley JAS, Garrick D, et al. Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet, 2003,34(2):157\u2013165","journal-title":"Nat Genet"},{"issue":"11","key":"2585_CR20","doi-asserted-by":"publisher","first-page":"e1000258","DOI":"10.1371\/journal.pgen.1000258","volume":"4","author":"KV Morris","year":"2008","unstructured":"Morris KV, Santoso S, Turner AM, et al. Bidirectional transcription directs both transcriptional gene activation and suppression in human cells. PLoS Genet, 2008,4(11):e1000258","journal-title":"PLoS Genet"},{"issue":"14","key":"2585_CR21","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1101\/gad.1324305","volume":"9","author":"E Bernstein","year":"2005","unstructured":"Bernstein E, Allis CD. RNA meets chromatin. Genes Dev, 2005,9(14):1635\u20131655","journal-title":"Genes Dev"},{"issue":"6","key":"2585_CR22","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/j.tig.2005.04.009","volume":"21","author":"KE Shearwin","year":"2005","unstructured":"Shearwin KE, Callen BP, Egan JB. Transcriptional interference\u2014a crash course. Trends Genet, 2005,21(6):339\u2013345","journal-title":"Trends Genet"},{"issue":"9","key":"2585_CR23","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.tcb.2006.07.007","volume":"16","author":"M Squatrito","year":"2006","unstructured":"Squatrito M, Gorrini C, Amati B. Tip60 in DNA damage response and growth control: many tricks in one HAT. Trends Cell Biol, 2006,16(9):433\u2013442","journal-title":"Trends Cell Biol"},{"issue":"2","key":"2585_CR24","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s13353-018-0432-y","volume":"59","author":"AH Ghobashi","year":"2018","unstructured":"Ghobashi AH, Kamel MA. Tip60: updates. J Appl Genet, 2018,59(2):161\u2013168","journal-title":"J Appl Genet"},{"issue":"37","key":"2585_CR25","doi-asserted-by":"publisher","first-page":"13182","DOI":"10.1073\/pnas.0504211102","volume":"102","author":"Y Sun","year":"2005","unstructured":"Sun Y, Jiang X, Chen S, et al. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci USA, 2005,102(37):13182\u201313187","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Current Medical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11596-022-2585-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11596-022-2585-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11596-022-2585-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,13]],"date-time":"2022-08-13T16:18:30Z","timestamp":1660407510000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11596-022-2585-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,5]]},"references-count":25,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["2585"],"URL":"https:\/\/doi.org\/10.1007\/s11596-022-2585-5","relation":{},"ISSN":["2096-5230","2523-899X"],"issn-type":[{"value":"2096-5230","type":"print"},{"value":"2523-899X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,5]]},"assertion":[{"value":"12 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 July 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest Statement"}},{"value":"Author Xiao HAN is a member of the Editorial Board for Current Medical Science. The paper was handled by other editors and has undergone rigorous peer review process. Author Xiao HAN was not involved in the journal\u2019s review of, or decision related to, this manuscript.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest Statement"}}]}}