The transcription of the catalytic subunit of telomerase, TERT, is regulated differently in cancers with TERT promoter mutations. In these mutants, the housekeeping transcription factor GABPa/b1L (likely as a heterotetramer) is recruited to the mutation. This coincides with lower levels of DNA methylation (5mC) and lower PRC2 occupancy.
As these TERT promoter mutations are typically heterozygous, these cells also harbor a transcriptionally inactive allele of TERT, making these cells a unique model for studying TERT regulation. These silent alleles exhibit elevated levels of both PRC2 and 5mC, suggesting that these two marks of epigenetic silencing may cooperate to maintain the heterochromatic state of the silent allele.
Telomerase is assembled with hTR and accessory proteins (such as TCAB1) and traffics to Cajal bodies followed by recruitment to telomeres. Recent data suggest that telomerase if freely diffusing in the nucleus and when the enzyme encounters a telomere that is competent for lengthening, telomerase binds and extends. Binding of telomerase to telomeres involves interactions both with TPP1 and with the single stranded DNA at the chromosome terminus. Each of these two interactions are necessary but not sufficient on their own for telomere lengthening by telomerase, suggesting that additional factors are at play. These include numerous kinases, the precise roles of which are the subject of significant research efforts by multiple labs.
As in yeast, human telomerase recruitment to telomeres in cancer cells appears to rely on signaling from the DNA damage response (DDR) pathway. This suggests that telomerase is a specialized arm of the DDR. Specifically, the catalytic activity of the ATM and ATR kinases, which are major regulators of the DDR, are required for telomerse recruitment.
1. Tong A.S.*, Stern J.L.*, Sfeir A., Kartawinata M., de Lange T. Zhu X-D., Bryan T.M. ATM and ATR Signalling Regulate the Recruitment of Human Telomerase to Telomeres. Cell Reports. 13, 1633-46 (2015). https://doi.org/10.1016/j.celrep.2015.10.041
2. Stern J.L., Zyner K.G., Pickett H.A., Cohen S.B., Bryan T.M. Telomerase recruitment requires both TCAB1 and Cajal bodies independently. Mol. Cell Biol. 32, 2384-95,(2012).
3. Stern, J.L., Bryan, T.M. Telomerase recruitment to telomeres. Cytogenetic and Genome Res., 122, 243-254 (2008).
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