Rearrangement of upstream sequences of the hTERT gene during cellular immortalization

Telomerase expression, resulting from transcriptional activation of the hTERT gene, allows cells to acquire indefinite proliferative potential during cellular immortalization and tumorigenesis. However, mechanisms of hTERT gene activation in many immortal cell lines and cancer cells are poorly under...

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Published in:Genes chromosomes & cancer 2009-11, Vol.48 (11), p.963-974
Main Authors: Zhao, Yuanjun, Wang, Shuwen, Popova, Evgenya Y., Grigoryev, Sergei A., Zhu, Jiyue
Format: Article
Language:English
Subjects:
Acetylation
Cell Line, Transformed
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Chromatin - metabolism
Chromosome Breakage
Deoxyribonuclease I - metabolism
Fibroblasts
Gene Dosage
Gene Rearrangement
Histones - metabolism
Humans
In Situ Hybridization, Fluorescence
Models, Genetic
Mutation
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Telomerase - biosynthesis
Telomerase - genetics
Telomerase - metabolism
Transcription, Genetic
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Summary:Telomerase expression, resulting from transcriptional activation of the hTERT gene, allows cells to acquire indefinite proliferative potential during cellular immortalization and tumorigenesis. However, mechanisms of hTERT gene activation in many immortal cell lines and cancer cells are poorly understood. Here, we report our studies on hTERT activation using genetically related pairs of telomerase‐negative (Tel−) and ‐positive (Tel+) fibroblast lines. First, whereas transiently transfected plasmid reporters did not recapitulate the endogenous hTERT promoter, the promoter in chromosomally integrated bacterial artificial chromosome (BAC) reporters was activated in a subset of Tel+ cells, indicating that activation of the hTERT promoter required native chromatin context and/or distal regulatory elements. Second, the hTERT gene, located near the telomere of chromosome 5p, was translocated in all three Tel+ cell lines but not in their parental precrisis cells and Tel− immortal siblings. The breakage points were mapped to regions upstream of the hTERT promoter, indicating that the hTERT gene was the target of these chromosomal rearrangements. In two Tel+ cell lines, translocation of the endogenous hTERT gene appeared to be the major mechanism of its activation as the activity of hTERT promoter in many chromosomally integrated BAC reporters, with intact upstream and downstream neighboring loci, remained relatively low. Therefore, our results suggest that rearrangement of upstream sequences is an important new mechanism of hTERT promoter activation during cellular immortalization. The chromosomal rearrangements likely occurred during cellular crisis and facilitated by telomere dysfunction. Such translocations allowed the hTERT promoter to escape from the native condensed chromatin environment. © 2009 Wiley‐Liss, Inc.
ISSN:1045-2257
1098-2264
DOI:10.1002/gcc.20698