Abstract
Mammalian telomeres consist of tandem DNA repeats that bind protective protein factors collectively termed shelterins. Telomere disruption typically results in genome instability induced by telomere fusions. The mechanism of telomere fusion varies depending on the means of telomere disruption. Here, we investigate telomere fusions caused by overexpression of mutant telomerases that add mutated telomeric repeats, thereby compromising shelterin binding to telomeric termini. While all mutant telomeric sequences tested induced heterodicentric chromosome fusions in ATM-competent cells, only those mutant repeat sequences with significant self complementarity induced ATM-independent sister chromatid and isodicentric chromosome fusions. Thus, once a telomere becomes dysfunctional, the terminal telomeric sequence itself determines the fate of that telomere. These results suggest that annealing of self-complementary DNA sequence engages an alternative telomere fusion pathway in human cells, and provide one explanation for the conspicuous lack of self complementarity in the majority of known naturally occurring eukaryotic telomeric sequences.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 307-314 |
| Number of pages | 8 |
| Journal | Molecular Cell |
| Volume | 39 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 2010 |
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Keywords
- DNA
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
The terminal telomeric DNA sequence determines the mechanism of dysfunctional telomere fusion. / Stohr, Bradley A.; Xu, Lifeng; Blackburn, Elizabeth H.
In: Molecular Cell, Vol. 39, No. 2, 07.2010, p. 307-314.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The terminal telomeric DNA sequence determines the mechanism of dysfunctional telomere fusion
AU - Stohr, Bradley A.
AU - Xu, Lifeng
AU - Blackburn, Elizabeth H.
PY - 2010/7
Y1 - 2010/7
N2 - Mammalian telomeres consist of tandem DNA repeats that bind protective protein factors collectively termed shelterins. Telomere disruption typically results in genome instability induced by telomere fusions. The mechanism of telomere fusion varies depending on the means of telomere disruption. Here, we investigate telomere fusions caused by overexpression of mutant telomerases that add mutated telomeric repeats, thereby compromising shelterin binding to telomeric termini. While all mutant telomeric sequences tested induced heterodicentric chromosome fusions in ATM-competent cells, only those mutant repeat sequences with significant self complementarity induced ATM-independent sister chromatid and isodicentric chromosome fusions. Thus, once a telomere becomes dysfunctional, the terminal telomeric sequence itself determines the fate of that telomere. These results suggest that annealing of self-complementary DNA sequence engages an alternative telomere fusion pathway in human cells, and provide one explanation for the conspicuous lack of self complementarity in the majority of known naturally occurring eukaryotic telomeric sequences.
AB - Mammalian telomeres consist of tandem DNA repeats that bind protective protein factors collectively termed shelterins. Telomere disruption typically results in genome instability induced by telomere fusions. The mechanism of telomere fusion varies depending on the means of telomere disruption. Here, we investigate telomere fusions caused by overexpression of mutant telomerases that add mutated telomeric repeats, thereby compromising shelterin binding to telomeric termini. While all mutant telomeric sequences tested induced heterodicentric chromosome fusions in ATM-competent cells, only those mutant repeat sequences with significant self complementarity induced ATM-independent sister chromatid and isodicentric chromosome fusions. Thus, once a telomere becomes dysfunctional, the terminal telomeric sequence itself determines the fate of that telomere. These results suggest that annealing of self-complementary DNA sequence engages an alternative telomere fusion pathway in human cells, and provide one explanation for the conspicuous lack of self complementarity in the majority of known naturally occurring eukaryotic telomeric sequences.
KW - DNA
UR - http://www.scopus.com/inward/record.url?scp=77955495035&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77955495035&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2010.06.020
DO - 10.1016/j.molcel.2010.06.020
M3 - Article
VL - 39
SP - 307
EP - 314
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 2
ER -