A translocation-defective telomerase with low levels of activity and processivity stabilizes short telomeres and confers immortalization
Language: 
English
Abstract: 

Short, repetitive, G-rich telomeric sequences are synthesized by telomerase, a ribonucleoprotein consisting of telomerase reverse transcriptase (TERT) and an integrally associated RNA. Human TERT (hTERT) can repetitively reverse transcribe its RNA template, acting processively to add multiple telomeric repeats onto the same substrate. We investigated whether certain threshold levels of telomerase activity and processivity are required to maintain telomere function and immortalize human cells with limited lifespan. We assessed hTERT variants with mutations in motifs implicated in processivity and interaction with DNA, namely the insertion in fingers domain (V791Y), and the E primer grip motif (W930F). hTERT-W930F and hTERT-V791Y reconstitute reduced levels of DNA synthesis and processivity compared with wild-type telomerase. Of interest, hTERT-W930F is more defective in translocation than hTERT-V791Y. Nonetheless, hTERT-W930F, but not hTERT-V791Y, immortalizes limited-lifespan human cells. Both hTERT-W930F- and hTERT-V791Y-expressing cells harbor short telomeres, measured as signal free ends (SFEs), yet SFEs persist only in hTERT-V791Y cells, which undergo apoptosis, likely as a consequence of a defect in recruitment of hTERT-V791Y to telomeres. Our study is the first to demonstrate that low levels of DNA synthesis--on the order of 20% of wild-type telomerase levels--and extension of as few as three telomeric repeats are sufficient to maintain functional telomeres and immortalize limited-lifespan human cells.

Author(s): 
D'Souza, Yasmin
Chu, Tsz Wai
Autexier, Chantal
Item Type: 
Journal Article
Publication Title: 
Molecular Biology of the Cell
Journal Abbreviation: 
Mol. Biol. Cell
Publication Date: 
2013-05
Publication Year: 
2013
Pages: 
1469-1479
Volume: 
24
Issue: 
9
ISSN: 
1939-4586
DOI: 
10.1091/mbc.E12-12-0889
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 23447707 PMCID: PMC3639057

Turabian/Chicago Citation

Yasmin D'Souza, Tsz Wai Chu and Chantal Autexier. 2013-05. "A translocation-defective telomerase with low levels of activity and processivity stabilizes short telomeres and confers immortalization." Molecular Biology of the Cell 24: 9: 1469-1479. 10.1091/mbc.E12-12-0889.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1091/mbc.E12-12-0889 | issn = 1939-4586 | volume = 24 | pages = 1469-1479 | last = D'Souza | first = Yasmin | coauthors = Chu, Tsz Wai, Autexier, Chantal | title = A translocation-defective telomerase with low levels of activity and processivity stabilizes short telomeres and confers immortalization | journal = Molecular Biology of the Cell | date = 2013-05 | pmid = | pmc = }} </ref>