Telomere elongation through hTERT immortalisation leads to chromosome repositioning in control cells and genomic instability in Hutchinson-Gilford Progeria syndrome fibroblasts, expressing a novel SUN1 isoform.
Year: 2018
Type: article
Abstract: Immortalising primary cells with hTERT has been common practice to enable \nprimary cells to be of extended use in the laboratory since they avoid replicative \nsenescence. Studying exogenously expressed hTERT in cells also affords scientists \nmodels of early carcinogenesis and telomere behaviour. \nControl and the premature ageing disease - Hutchinson-Gilford Progeria Syndrome \nprimary dermal fibroblasts, with and without the classical G608G mutation have been \nimmortalised with exogenous hTERT. However, hTERT immortalisation surprisingly \nelicits genome reorganisation, in disease cells but also in the normal control cells, \nsuch that whole chromosome territories normally located at the nuclear periphery in \nproliferating fibroblasts become mis-localised in the nuclear interior. This includes \nchromosome 18 in the control fibroblasts and both chromosomes 18 and X in HGPS \ncells, which physically express an isoform of the LINC complex protein SUN1 that \nhas previously only been theoretical. Additionally, this HGPS cell line has also \nbecome genomically unstable and has a tetraploid karyotype, which could be due to \nthe novel SUN1 isoform. \nLong term treatment with the hTERT inhibitor BIBR1532 enabled the reduction of \ntelomere length in the immortalised cells and resulted in these mis-localised internal \nchromosomes to be located at the nuclear periphery, as assessed in actively \nproliferating cells. \nTaken together, these findings reveal that elongated telomeres lead to dramatic \nchromosome mis-localisation, which can be restored with a drug treatment that \nresults in telomere re-shortening and that a novel SUN1 isoform combined with elongated telomeres leads to genomic instability. Thus, care should be taken when \ninterpreting data from genomic studies in hTERT immortalised cell lines.
Authors: Bridger, JM, Makarov, E, Anderson, R
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6996875591