Abstract
Telomere, the terminus of linear chromosome in eukaryotes, is composed of specific repeat DNA which is mainly synthesized by a protein complex called telomerase. The maintenance of telomere DNA is important for unlimited proliferative capacity of cancer cells. The telomerase activity is controlled by the expression level of telomerase reverse transcriptase (TERT), a catalytic unit of telomerase, in some species including human. Therefore, to reveal the regulatory mechanisms of the transcription of TERT gene is important for understanding the tumor development. We found that template activating factor-I (TAF-I), a multifunctional nuclear protein, is involved in the transcriptional activation of TERT for the maintenance of telomere DNA in HeLa cells. TAF-I maintains the histone H3 modifications involved in transcriptional activation and hypomethylated cytosines in CpG dinucleotides around the transcription start site (TSS) in the TERT gene locus. Collectively, TAF-I is involved in the maintenance of telomere DNA through the regulation of TERT transcription, then consequently the occurrence and/or recurrence of cancer cells.
Highlights
Telomeres are located at the ends of chromosome and have specific repetitive DNA sequence in eukaryotes
We found that Template activating factor-I (TAF-I) is a novel regulator of telomere DNA synthesis through the transcriptional activation of telomerase reverse transcriptase (TERT) through epigenetic mechanism in human cancer cells
We found that TAF-I knock down (KD) enhanced the methylation level of CpG dinucleotides around the transcription start site (TSS) including minimal core promoter, but not the upstream region overlapping to TERT hypermethylated oncological region (THOR), in the TERT locus in HeLa cells
Summary
Telomeres are located at the ends of chromosome and have specific repetitive DNA sequence in eukaryotes. Several nucleotide mutations are frequently introduced in the TERT promoter region and implicated in telomerase reactivation in cancer cells by the de novo binding sites for ETS family transcription factors such as GABP8–10. In addition to such somatic mutations, amplification of TERT gene[11,12] and rearrangement of TERT locus[13,14] directing its transcriptional activation are reported during cancer development. We found that TAF-I maintains the telomere integrity through the epigenetic regulation of the TERT gene transcription in human cancer cells. We proposed that TAF-I is involved in the occurrence and/or recurrence of cancer cells by telomerase reactivation through the epigenetic mechanisms
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