Inactive C-terminal telomerase reverse transcriptase insertion splicing variants are dominant-negative inhibitors of telomerase

摘要: Maintenance of telomere length and structure is essential for cell survival. Telomere synthesis mediated by the ribonucleoprotein telomerase in 90% cancer cells, regulated mainly transcription human reverse transcriptase subunit, hTERT. However, transcriptome analysis reveals complex splicing patterns to date, twenty-two alternatively-spliced hTERT mRNAs have been reported, yet their functions not fully elucidated. The best characterized spliced variants encode inactive proteins that possess specific deletions within catalytic domains. We studied two less well splice (termed INS3 4) with intact motifs, but alternative C-domains due insertion intronic sequences. determined prevalence these mRNA primary telomerase-positive cells lengthening (ALT) found transcripts be expressed lines translated into as illustrated association polysomes. These were when vitro or retained DNA substrate binding impaired RNA component in, immunoprecipitated from either telomerase-negative ALT coexpressing component. Stable expression INS4 a hepatocarcinoma line inhibited activity, shortened telomeres slowed growth suggesting potential dominant-negative function.