{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T17:10:44Z","timestamp":1770138644454,"version":"3.49.0"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2018,4,17]],"date-time":"2018-04-17T00:00:00Z","timestamp":1523923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Natural Science Foundation of China","award":["81670848 & 81470626"],"award-info":[{"award-number":["81670848 & 81470626"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Previous studies have reported that Brca1 acts as a \u201chinge\u201d in the development of the central nervous system (CNS). However, the precise role of Brca1 in rat retinal neurons remains unclear. Here, we found that Brca1 is developmentally downregulated and silenced in adult retina. Brca1 was upregulated in rat primary retinal neurons by 5-Aza-2\u2032-deoxycytidine (5-Aza-CdR) treatment. Moreover, the upregulation of Brca1 by both 5-Aza-CdR and transgenic Brca1 promoted genomic stability and improved cell viability following exposure to ionizing radiation (IR). Furthermore, transgenic Brca1 significantly inhibited neurite outgrowth of retinal neurons, which implicates that Brca1 silencing promotes cell differentiation and determines neuronal morphology. Taken together, our results reveal a biological function of Brca1 in retinal development.<\/jats:p>","DOI":"10.3390\/ijms19041214","type":"journal-article","created":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T03:51:13Z","timestamp":1524023473000},"page":"1214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Brca1 Is Upregulated by 5-Aza-CdR and Promotes DNA Repair and Cell Survival, and Inhibits Neurite Outgrowth in Rat Retinal Neurons"],"prefix":"10.3390","volume":"19","author":[{"given":"Qiyun","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuojun","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Qiu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Ge","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keming","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Zhuang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1126\/science.7545954","article-title":"A strong candidate for the breast and ovarian cancer susceptibility gene brca1","volume":"266","author":"Miki","year":"1994","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1093\/nar\/gkl010","article-title":"Brca1: Cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution","volume":"34","author":"Deng","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1111\/j.1742-4658.2010.07734.x","article-title":"Brca1 16 years later: DNA damage-induced brca1 shuttling","volume":"277","author":"Yang","year":"2010","journal-title":"FEBS J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/nature07955","article-title":"Ctip-brca1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle","volume":"459","author":"Yun","year":"2009","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1158\/0008-5472.CAN-05-3278","article-title":"Checkpoint kinase 2-mediated phosphorylation of brca1 regulates the fidelity of nonhomologous end-joining","volume":"66","author":"Zhuang","year":"2006","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1126\/science.286.5442.1162","article-title":"Requirement of atm-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks","volume":"286","author":"Cortez","year":"1999","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1667\/RR14532.1","article-title":"Intrinsic line-1 hypomethylation and decreased brca1 expression are associated with DNA repair delay in irradiated thyroid cells","volume":"188","author":"Penha","year":"2017","journal-title":"Radiat. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5854","DOI":"10.1038\/sj.onc.1209872","article-title":"The role of brca1 in transcriptional regulation and cell cycle control","volume":"25","author":"Mullan","year":"2006","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1002\/jnr.10546","article-title":"Tumor suppressor gene Brca-1 is expressed by embryonic and adult neural stem cells and involved in cell proliferation","volume":"71","author":"Korhonen","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1242\/dev.033498","article-title":"Brca1 is required for embryonic development of the mouse cerebral cortex to normal size by preventing apoptosis of early neural progenitors","volume":"136","author":"Pulvers","year":"2009","journal-title":"Development"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1101\/gad.309404","article-title":"Chromatin remodeling and histone modification in the conversion of oligodendrocyte precursors to neural stem cells","volume":"18","author":"Kondo","year":"2004","journal-title":"Genes Dev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1073\/pnas.1212563110","article-title":"Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons","volume":"110","author":"Keimpema","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/nn.3537","article-title":"Maintaining genome stability in the nervous system","volume":"16","author":"Mckinnon","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nature02661","article-title":"Gene regulation and DNA damage in the ageing human brain","volume":"429","author":"Lu","year":"2004","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.dnarep.2013.04.008","article-title":"DNA strand break repair and neurodegeneration","volume":"12","author":"Rulten","year":"2013","journal-title":"DNA Repair"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chen, P., Hu, H., Chen, Z., Cai, X., Zhang, Z., Yang, Y., Yu, N., Zhang, J., Xia, L., and Ge, J. (2014). Brca1 silencing is associated with failure of DNA repairing in retinal neurocytes. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099371"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"140","DOI":"10.7150\/ijms.4.140","article-title":"Brca1 may modulate neuronal cell cycle re-entry in alzheimer disease","volume":"4","author":"Evans","year":"2007","journal-title":"Int. J. Med. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1126\/science.1152662","article-title":"Design logic of a cannabinoid receptor signaling network that triggers neurite outgrowth","volume":"320","author":"Bromberg","year":"2008","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.neuron.2007.02.022","article-title":"Covalent modification of DNA regulates memory formation","volume":"53","author":"Miller","year":"2007","journal-title":"Neuron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.neuron.2017.04.022","article-title":"The dynamic epigenetic landscape of the retina during development, reprogramming, and tumorigenesis","volume":"94","author":"Aldiri","year":"2017","journal-title":"Neuron"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11950","DOI":"10.1128\/JVI.01406-09","article-title":"5-azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1","volume":"83","author":"Dapp","year":"2009","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1743-422X-9-1","article-title":"Antiretroviral activity of 5-azacytidine during treatment of a htlv-1 positive myelodysplastic syndrome with autoimmune manifestations","volume":"9","author":"Diamantopoulos","year":"2012","journal-title":"Virol. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"229","DOI":"10.4161\/epi.5.3.11409","article-title":"5-azacytidine treatment reorganizes genomic histone modification patterns","volume":"5","author":"Komashko","year":"2010","journal-title":"Epigenetics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E1240","DOI":"10.1073\/pnas.1400783111","article-title":"Role of Brca1 in brain development","volume":"111","author":"Pao","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.redox.2015.11.005","article-title":"Breast cancer 1 (Brca1)-deficient embryos develop normally but are more susceptible to ethanol-initiated DNA damage and embryopathies","volume":"7","author":"Shapiro","year":"2016","journal-title":"Redox Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1523\/JNEUROSCI.16-03-00939.1996","article-title":"DNA mismatch repair and DNA methylation in adult brain neurons","volume":"16","author":"Brooks","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1046\/j.1471-4159.1999.0731164.x","article-title":"Oxidative damage to the c-fos gene and reduction of its transcription after focal cerebral ischemia","volume":"73","author":"Cui","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0921-8777(98)00018-4","article-title":"Detection of excision nuclease in cell-free extracts from the adult mammalian brain","volume":"408","author":"Brooks","year":"1998","journal-title":"Mutat. Res.\/DNA Repair"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6795","DOI":"10.1523\/JNEUROSCI.16-21-06795.1996","article-title":"Damage, repair, and mutagenesis in nuclear genes after mouse forebrain ischemia-reperfusion","volume":"16","author":"Liu","year":"1996","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1038\/nsmb.1941","article-title":"Transcriptional regulation of Brca1 expression by a metabolic switch","volume":"17","author":"Di","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11322","DOI":"10.1073\/pnas.0401355101","article-title":"Nuclear scaffold\/matrix attached region modules linked to a transcription unit are sufficient for replication and maintenance of a mammalian episome","volume":"101","author":"Jenke","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/4\/1214\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:00:58Z","timestamp":1760194858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/4\/1214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,17]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2018,4]]}},"alternative-id":["ijms19041214"],"URL":"https:\/\/doi.org\/10.3390\/ijms19041214","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,17]]}}}