Abstract
The reactivation of telomerase in cancer cells remains incompletely understood. The catalytic component of telomerase, hTERT, is thought to be the limiting component in cancer cells for the formation of active enzymes. hTERT gene expression is regulated at several levels including chromatin, DNA methylation, transcription factors, and RNA processing events. Of these regulatory events, RNA processing has received little attention until recently. RNA processing and alternative splicing regulation have been explored to understand how hTERT is regulated in cancer cells. The cis- and trans-acting factors that regulate the alternative splicing choice of hTERT in the reverse transcriptase domain have been investigated. Further, it was discovered that the splicing factors that promote the production of full-length hTERT were also involved in cancer cell growth and survival. The goals are to review telomerase regulation via alternative splicing and the function of hTERT splicing variants and to point out how bioinformatics approaches are leading the way in elucidating the networks that regulate hTERT splicing choice and ultimately cancer growth.
Highlights
Telomeres are specialized DNA and protein structures found at the ends of linear chromosomes made up of the hexameric repeat DNA 50 -TTAGGGn [1]
This alternative variant is in the canonical human TERT (hTERT) reading frame and codes for a dominant-negative protein that can interact with hTR, and when overexpressed, results in telomere shortening in telomerase positive cells [51]
A long-held paradigm in the telomere/telomerase field was and still is that hTERT and telomerase is regulated by transcription
Summary
Telomeres are specialized DNA and protein structures found at the ends of linear chromosomes made up of the hexameric repeat DNA 50 -TTAGGGn [1]. When a few telomeres have DNA damage at chromosome ends, deprotection occurs and cellular senescence is initiated This removes cells with critically short telomeres from the replicating population of cells and acts as a potent block to tumor progression. Due to the lack of telomerase activity in most normal cells, besides transit-amplifying stem cells and germ line cells, and the fact that the majority (~90%) of cancer cells have telomerase activity, telomerase has been a highly sought-after cancer therapeutic target While both public and private efforts have attempted to develop inhibitors of this enzyme, the most clinically progressed drug is an anti-sense RNA (Imeltelstat, GRN163L) of the template RNA, hTR [10,28,29,30]. Alternative splicing offers biological mechanism utilized by cells to of regulate theVariants
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