Dysfunctional mammalian telomeres join with DNA double-strand breaks - PubMed (original) (raw)
Dysfunctional mammalian telomeres join with DNA double-strand breaks
Susan M Bailey et al. DNA Repair (Amst). 2004.
Abstract
In addition to joining broken DNA strands, several non-homologous end-joining (NHEJ) proteins have a second seemingly antithetical role in constructing functional telomeres, the nucleoprotein structures at the termini of linear eukaryotic chromosomes that prevent joining between natural chromosome ends. Although NHEJ deficiency impairs double-strand break (DSB) repair, it also promotes inappropriate chromosomal end fusions that are observed microscopically as dicentric chromosomes with telomeric DNA sequence at points of joining. Here, we test the proposition that unprotected telomeres can fuse not only to other dysfunctional telomeres, but also to ends created by DSBs. Severe combined immunodeficiency (scid) is caused by a mutation in the catalytic subunit of DNA-dependent protein kinase (DNA-PK), an enzyme required for both efficient DSB repair and telomeric end-capping. Cells derived from wild-type, Trp53-/-, scid, and Trp53-/-/scid mice were exposed to gamma radiation to induce DSBs, and chromosomal aberrations were analyzed using a novel cytogenetic technique that can detect joining of a telomere to a DSB end. Telomere-DSB fusions were observed in both cell lines having the scid mutation, but not in wild-type nor Trp53-/- cells. Over a range of 25-340 cGy, half of the visible exchange-type chromosomal aberrations in Trp53-/-/scid cells involved telomere-DSB fusions. Our results demonstrate that unprotected telomeres are not only sensed as, but also acted upon, by the DNA repair machinery as if they were DSB ends. By opening a new pathway for misrepair, telomere-DSB fusion decreases the overall fidelity of DSB repair. The high frequency of these events in scid cells indicates telomere dysfunction makes a strong, and previously unsuspected, contribution to the characteristic radiation sensitivity associated with DNA-PK deficiency.
Similar articles
- The kinase activity of DNA-PK is required to protect mammalian telomeres.
Bailey SM, Brenneman MA, Halbrook J, Nickoloff JA, Ullrich RL, Goodwin EH. Bailey SM, et al. DNA Repair (Amst). 2004 Mar 4;3(3):225-33. doi: 10.1016/j.dnarep.2003.10.013. DNA Repair (Amst). 2004. PMID: 15177038 - Shortened telomeres in murine scid cells expressing mutant hRAD54 coincide with reduction in recombination at telomeres.
Al-Wahiby S, Wong HP, Slijepcevic P. Al-Wahiby S, et al. Mutat Res. 2005 Oct 15;578(1-2):134-42. doi: 10.1016/j.mrfmmm.2005.04.008. Epub 2005 Jun 21. Mutat Res. 2005. PMID: 15975611 - DNA and telomeres: beginnings and endings.
Bailey SM, Goodwin EH. Bailey SM, et al. Cytogenet Genome Res. 2004;104(1-4):109-15. doi: 10.1159/000077474. Cytogenet Genome Res. 2004. PMID: 15162023 Review. - Telomeres and the DNA damage response: why the fox is guarding the henhouse.
Maser RS, DePinho RA. Maser RS, et al. DNA Repair (Amst). 2004 Aug-Sep;3(8-9):979-88. doi: 10.1016/j.dnarep.2004.05.009. DNA Repair (Amst). 2004. PMID: 15279784 Review.
Cited by
- Chromosomal Instability as Enabling Feature and Central Hallmark of Breast Cancer.
Castellanos G, Valbuena DS, Pérez E, Villegas VE, Rondón-Lagos M. Castellanos G, et al. Breast Cancer (Dove Med Press). 2023 Mar 9;15:189-211. doi: 10.2147/BCTT.S383759. eCollection 2023. Breast Cancer (Dove Med Press). 2023. PMID: 36923397 Free PMC article. Review. - Using telomeric chromosomal aberrations to evaluate clastogen-induced genomic instability in mammalian cells.
Bolzán AD. Bolzán AD. Chromosome Res. 2020 Dec;28(3-4):259-276. doi: 10.1007/s10577-020-09641-2. Epub 2020 Sep 17. Chromosome Res. 2020. PMID: 32940874 Review. - Tumor Cell-Accelerated Senescence Is Associated With DNA-PKcs Status and Telomere Dysfunction Induced by Radiation.
Zhang M, Guo X, Gao Y, Lu D, Li W. Zhang M, et al. Dose Response. 2018 Apr 23;16(2):1559325818771527. doi: 10.1177/1559325818771527. eCollection 2018 Apr-Jun. Dose Response. 2018. PMID: 29760601 Free PMC article. - DNA repair kinetics in SCID mice Sertoli cells and DNA-PKcs-deficient mouse embryonic fibroblasts.
Ahmed EA, Vélaz E, Rosemann M, Gilbertz KP, Scherthan H. Ahmed EA, et al. Chromosoma. 2017 Mar;126(2):287-298. doi: 10.1007/s00412-016-0590-9. Epub 2016 May 2. Chromosoma. 2017. PMID: 27136939 Free PMC article. - Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis.
Sishc BJ, Nelson CB, McKenna MJ, Battaglia CL, Herndon A, Idate R, Liber HL, Bailey SM. Sishc BJ, et al. Front Oncol. 2015 Nov 24;5:257. doi: 10.3389/fonc.2015.00257. eCollection 2015. Front Oncol. 2015. PMID: 26636039 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
Research Materials