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The mutation produces an abnormal lamin A protein called progerin that lacks the splice site necessary to remove a farnesylated domain. Subsequently, progerin accumulates in the nuclear envelope, disrupting nuclear architecture, chromatin organization, and gene expression. These alterations are often associated with rapid telomere erosion and cellular aging. Here, we further characterize the cellular and molecular abnormalities in HGPS cells and report a significant reversal of some of these abnormalities by introduction of in vitro transcribed and purified human telomerase (hTERT) mRNA. There is intra\u2010individual heterogeneity of expression of telomere\u2010associated proteins DNA PKcs\/Ku70\/Ku80, with low\u2010expressing cells having shorter telomeres. In addition, the loss of the heterochromatin marker H3K9me3 in progeria is associated with accelerated telomere erosion. In HGPS cell lines characterized by short telomeres, transient transfections with hTERT mRNA increase telomere length, increase expression of telomere\u2010associated proteins, increase proliferative capacity and cellular lifespan, and reverse manifestations of cellular senescence as assessed by \u03b2\u2010galactosidase expression and secretion of inflammatory cytokines. Unexpectedly, mRNA hTERT also improves nuclear morphology. In combination with the farnesyltransferase inhibitor (FTI) lonafarnib, hTERT mRNA promotes HGPS cell proliferation. Our findings demonstrate transient expression of human telomerase in combination with FTIs could represent an improved therapeutic approach for HGPS.<\/jats:p>","DOI":"10.1111\/acel.12979","type":"journal-article","created":{"date-parts":[[2019,6,1]],"date-time":"2019-06-01T04:14:58Z","timestamp":1559362498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Transient introduction of human telomerase mRNA improves hallmarks of progeria cells"],"prefix":"10.1111","volume":"18","author":[{"given":"Yanhui","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cell Biology UT Southwestern Medical Center Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences Houston Methodist Research Institute Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivone G.","family":"Bruno","sequence":"additional","affiliation":[{"name":"Lonza Walkersville Inc. Walkersville Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology UT Southwestern Medical Center Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sei","family":"Sho","sequence":"additional","affiliation":[{"name":"Department of Cell Biology UT Southwestern Medical Center Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Tedone","sequence":"additional","affiliation":[{"name":"Department of Cell Biology UT Southwestern Medical Center Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung\u2010Po","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Cell Biology UT Southwestern Medical Center Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Cooke","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Sciences Houston Methodist Research Institute Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5052-0627","authenticated-orcid":false,"given":"Jerry W.","family":"Shay","sequence":"additional","affiliation":[{"name":"Department of Cell Biology UT Southwestern Medical Center Dallas Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,5,31]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1952"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.067306"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2004.02.002"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2016.1179409"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002346"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506001102"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1444"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.07759"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9728.2004.00105.x"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1346005"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2009.03.001"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01629"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402943101"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1202529109"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00504-9"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e08-05-0492"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01291-z"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.06.017"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09879"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku439"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.11.5050-5059.2004"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.05.009"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-259531"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.251041.114"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1909"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00355-08"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1708"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0062"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602569103"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.3080"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.37.110801.142705"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12859"},{"key":"e_1_2_7_34_1","volume-title":"Relationships between nuclear lamins and telomere biology in progeroid laminopathies and cancer","author":"Turner R.","year":"2014"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2008.00382.x"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903362106"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6467"},{"key":"e_1_2_7_38_1","volume-title":"Structure\u2010function analysis of the human telomerase reverse transcriptase","author":"Wyatt H. 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