f45198c14902db7b9e3024a7f81c4aef ijms_a2018v19n7p2078.pdf da8c75262f9f68bfb43338bd0eede98fa3d61974 ijms_a2018v19n7p2078.pdf 61db4e315c16572341a4f4707e4a898a2c4007b3b47a0f3f666777ee15cbb6e0 ijms_a2018v19n7p2078.pdf Title: Generation of Immortalised But Unstable Cells after hTERT Introduction in Telomere-Compromised and p53-Deficient vHMECs Subject: Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse and unmasked telomeres. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptosis, but they can also promote tumour initiation when cell cycle checkpoints are disabled. In this setting, telomere dysfunction promotes increasing chromosome instability (CIN) through breakage-fusion-bridge cycles. Excessive instability may hamper cell proliferation but might allow for the appearance of some rare advantageous mutations that could be selected and ultimately favour neoplastic progression. With the aim of generating pre-malignant immortalised cells, we ectopically expressed telomerase in telomere-compromised variant human mammary epithelial cells (vHMECs), proficient and deficient for p53, and analysed structural and numerical chromosomal aberrations as well as abnormal nuclear morphologies. Importantly, this study provides evidence that while immortalisation of vHMECs at early stages results in an almost stable karyotype, a transient telomere-dependent CIN period—aggravated by p53 deficiency—and followed by hTERT overexpression serves as a mechanism for the generation of immortal unstable cells which, due to their evolving karyotype, could attain additional promoting properties permissive to malignancy. Keywords: human mammary epithelial cells; telomere dysfunction; chromosome instability; p53; hTERT; cancer Author: Aina Bernal, Elisenda Zafon, Daniel Domínguez, Enric Bertran and Laura Tusell Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.17 CreationDate: Tue Jul 17 13:03:16 2018 CEST ModDate: Tue Jul 17 13:03:16 2018 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2458315 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SKTRPM+URWPalladioL-Ital Type 1 Custom yes yes no 115 0 BPXBTB+URWPalladioL-Bold Type 1 Custom yes yes no 116 0 OXBKYU+TeXGyreAdventor-Bold Type 1 Custom yes yes no 117 0 WLENKM+VnURWPalladioL-Bold Type 1 Custom yes yes no 118 0 CVJWJT+URWPalladioL-Roma Type 1 Custom yes yes no 119 0 DYVFWR+CMSY10 Type 1 Builtin yes yes no 120 0 EMWSBR+VnURWPalladioL Type 1 Custom yes yes no 121 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 126 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 127 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 142 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 143 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 144 0 MDJLZU+EURM10 Type 1 Builtin yes yes no 215 0 MKHAFK+PalatinoLinotype TrueType WinAnsi yes yes no 220 0 MKHAIK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 221 0 MKHAIM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 222 0 MKHBCK+TimesNewRoman TrueType WinAnsi yes yes no 223 0 MKHAFJ+PalatinoLinotype CID TrueType Identity-H yes yes yes 248 0 MKHAFK+PalatinoLinotype TrueType WinAnsi yes yes no 249 0 MKHAIK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 250 0 MKHAIM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 251 0 MKHBCK+TimesNewRoman TrueType WinAnsi yes yes no 252 0 MKHAFK+PalatinoLinotype TrueType WinAnsi yes yes no 340 0 MKHAIK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 341 0 MKHAIM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 342 0 MKHBCK+TimesNewRoman TrueType WinAnsi yes yes no 343 0 MKHAFK+PalatinoLinotype TrueType WinAnsi yes yes no 397 0 MKHAIK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 398 0 MKHAIM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 399 0 MKHBCK+TimesNewRoman TrueType WinAnsi yes yes no 400 0 MKHAFK+PalatinoLinotype TrueType WinAnsi yes yes no 425 0 MKHAIK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 426 0 MKHAIM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 427 0 MKHBCK+TimesNewRoman TrueType WinAnsi yes yes no 428 0 MKHAFJ+PalatinoLinotype CID TrueType Identity-H yes yes yes 501 0 MKHAFK+PalatinoLinotype TrueType WinAnsi yes yes no 502 0 MKHAIK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 503 0 MKHAIM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 504 0 MKHBCK+TimesNewRoman TrueType WinAnsi yes yes no 505 0 ESSRQF+VnURWPalladioL-Italic Type 1 Custom yes yes no 568 0 java.lang.ClassCastException: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject cannot be cast to edu.harvard.hul.ois.jhove.module.pdf.PdfDictionary at edu.harvard.hul.ois.jhove.module.PdfModule.readDocCatalogDict(PdfModule.java:1284) at edu.harvard.hul.ois.jhove.module.PdfModule.parse(PdfModule.java:525) at edu.harvard.hul.ois.jhove.JhoveBase.processFile(JhoveBase.java:825) at edu.harvard.hul.ois.jhove.JhoveBase.process(JhoveBase.java:614) at edu.harvard.hul.ois.jhove.JhoveBase.dispatch(JhoveBase.java:465) at Jhove.main(Jhove.java:296) Jhove (Rel. 1.6, 2011-01-04) Date: 2019-02-14 17:32:49 CET RepresentationInformation: ijms_a2018v19n7p2078.pdf ReportingModule: BYTESTREAM, Rel. 1.3 (2007-04-10) LastModified: 2019-01-29 10:34:51 CET Size: 2458315 Format: bytestream Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/octet-stream Checksum: 7224e6a2 Type: CRC32 Checksum: f45198c14902db7b9e3024a7f81c4aef Type: MD5 Checksum: da8c75262f9f68bfb43338bd0eede98fa3d61974 Type: SHA-1