TRF2 Interaction with Ku Heterotetramerization Interface Gives Insight into c-NHEJ Prevention at Human Telomeres
Telomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku’s association with telomeric ends, thus inhibiting c-NH...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-10-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713004816 |
| _version_ | 1818568985631784960 |
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| author | Albert Ribes-Zamora Sandra M. Indiviglio Ivana Mihalek Christopher L. Williams Alison A. Bertuch |
| author_facet | Albert Ribes-Zamora Sandra M. Indiviglio Ivana Mihalek Christopher L. Williams Alison A. Bertuch |
| author_sort | Albert Ribes-Zamora |
| collection | DOAJ |
| description | Telomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku’s association with telomeric ends, thus inhibiting c-NHEJ; however, deficiencies in the t-loop model suggest additional mechanisms are in effect. We demonstrate that TRF2 interacts with Ku at telomeres and via residues in Ku70 helix 5 (α5), which are vital for NHEJ. We show that Ku’s interaction with a TRF2 mutant that induces telomeric fusions is significantly impaired. Additionally, we demonstrate that Ku70 α5 is required for Ku self-association in live cells, which can bridge DNA ends. Together, these findings lead us to propose a model in which telomeres are directly protected from c-NHEJ via TRF2 impeding Ku’s ability to synapse telomere ends. |
| first_indexed | 2024-12-14T06:42:08Z |
| format | Article |
| id | doaj.art-d811764b3dbb421b8a1e85fde1ff1b84 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T06:42:08Z |
| publishDate | 2013-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-d811764b3dbb421b8a1e85fde1ff1b842022-12-21T23:13:11ZengElsevierCell Reports2211-12472013-10-015119420610.1016/j.celrep.2013.08.040TRF2 Interaction with Ku Heterotetramerization Interface Gives Insight into c-NHEJ Prevention at Human TelomeresAlbert Ribes-Zamora0Sandra M. Indiviglio1Ivana Mihalek2Christopher L. Williams3Alison A. Bertuch4Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USADepartment of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USABioinformatics Institute, Agency for Science, Technology and Research, 30 Biopolis Street, 07-01 Matrix, Singapore 138671, SingaporeDepartment of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USADepartment of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USATelomeres are protected from nonhomologous end-joining (NHEJ) to avoid deleterious chromosome fusions, yet they associate with the Ku heterodimer that is principal in the classical NHEJ (c-NHEJ) pathway. T-loops have been proposed to inhibit Ku’s association with telomeric ends, thus inhibiting c-NHEJ; however, deficiencies in the t-loop model suggest additional mechanisms are in effect. We demonstrate that TRF2 interacts with Ku at telomeres and via residues in Ku70 helix 5 (α5), which are vital for NHEJ. We show that Ku’s interaction with a TRF2 mutant that induces telomeric fusions is significantly impaired. Additionally, we demonstrate that Ku70 α5 is required for Ku self-association in live cells, which can bridge DNA ends. Together, these findings lead us to propose a model in which telomeres are directly protected from c-NHEJ via TRF2 impeding Ku’s ability to synapse telomere ends.http://www.sciencedirect.com/science/article/pii/S2211124713004816 |
| spellingShingle | Albert Ribes-Zamora Sandra M. Indiviglio Ivana Mihalek Christopher L. Williams Alison A. Bertuch TRF2 Interaction with Ku Heterotetramerization Interface Gives Insight into c-NHEJ Prevention at Human Telomeres Cell Reports |
| title | TRF2 Interaction with Ku Heterotetramerization Interface Gives Insight into c-NHEJ Prevention at Human Telomeres |
| title_full | TRF2 Interaction with Ku Heterotetramerization Interface Gives Insight into c-NHEJ Prevention at Human Telomeres |
| title_fullStr | TRF2 Interaction with Ku Heterotetramerization Interface Gives Insight into c-NHEJ Prevention at Human Telomeres |
| title_full_unstemmed | TRF2 Interaction with Ku Heterotetramerization Interface Gives Insight into c-NHEJ Prevention at Human Telomeres |
| title_short | TRF2 Interaction with Ku Heterotetramerization Interface Gives Insight into c-NHEJ Prevention at Human Telomeres |
| title_sort | trf2 interaction with ku heterotetramerization interface gives insight into c nhej prevention at human telomeres |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713004816 |
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