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Dysfunctional mammalian telomeres join with DNA double-strand breaks
Susan M Bailey1, Michael N Cornforth, Robert L Ullrich
1Department of Radiological Health Services, Colorado State University, Fort Collins, CO 80523-1618, USA.
DNA Repair
|March 11, 2004
Summary
Unprotected telomeres can fuse with DNA double-strand breaks (DSBs), a misrepair pathway particularly evident in DNA-PK deficient cells. This telomere-DSB fusion contributes to radiation sensitivity and impairs DNA repair fidelity.
Area of Science:
- Genetics
- Molecular Biology
- Cell Biology
Background:
- Non-homologous end-joining (NHEJ) proteins are crucial for DNA double-strand break (DSB) repair and telomere maintenance.
- NHEJ deficiency can lead to chromosomal end fusions, forming dicentric chromosomes with telomeric sequences.
Purpose of the Study:
- To investigate whether unprotected telomeres can fuse with DNA double-strand breaks (DSBs).
- To determine the role of DNA-dependent protein kinase (DNA-PK) deficiency in telomere-DSB fusions.
Main Methods:
- Exposure of wild-type, Trp53-/-, scid, and Trp53-/-/scid mouse cells to gamma radiation to induce DSBs.
- Analysis of chromosomal aberrations using a novel cytogenetic technique to detect telomere-DSB fusions.
Main Results:
- Telomere-DSB fusions were observed in scid mutant cell lines but not in wild-type or Trp53-/- cells.
- In Trp53-/-/scid cells, half of the observed exchange-type chromosomal aberrations involved telomere-DSB fusions.
- The frequency of telomere-DSB fusions was high in scid cells, indicating a contribution to radiation sensitivity.
Conclusions:
- Unprotected telomeres are recognized and processed by the DNA repair machinery as if they were DSB ends.
- Telomere-DSB fusion represents a novel misrepair pathway that decreases overall DSB repair fidelity.
- Telomere dysfunction significantly contributes to the radiation sensitivity observed in DNA-PK deficient cells.