Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining
Shelterin protects chromosome ends from the DNA damage response. Although the mechanism of telomere protection has been studied extensively, the fate of double-strand breaks (DSBs) inside telomeres is not known. Here, we report that telomere-internal FokI-induced DSBs activate ATM kinase-dependent s...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-11-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716313948 |
| _version_ | 1818057356351635456 |
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| author | Ylli Doksani Titia de Lange |
| author_facet | Ylli Doksani Titia de Lange |
| author_sort | Ylli Doksani |
| collection | DOAJ |
| description | Shelterin protects chromosome ends from the DNA damage response. Although the mechanism of telomere protection has been studied extensively, the fate of double-strand breaks (DSBs) inside telomeres is not known. Here, we report that telomere-internal FokI-induced DSBs activate ATM kinase-dependent signaling in S-phase but are well tolerated and repaired efficiently. Homologous recombination contributes to repair, leading to increased telomere length heterogeneity typical of the alternative lengthening of telomeres (ALT) pathway. Furthermore, cells accumulate extra chromosomal telomeric signals (ECTS), a second hallmark of ALT. Telomere-internal DSBs are also repaired by a PARP1- and Ligase3-dependent reaction, suggesting alternative non-homologous end-joining (alt-NHEJ), which relies on microhomology at DSBs. However, as resected telomere-internal DSBs have perfect homology, their PARP1/Lig3-dependent end-joining may be more akin to single strand break repair. We conclude that shelterin does not repress ATM kinase signaling or DSB repair at telomere-internal sites, thereby allowing DNA repair to maintain telomere integrity. |
| first_indexed | 2024-12-10T12:43:26Z |
| format | Article |
| id | doaj.art-844f2f24122741e2a43b89e3c0215c7e |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T12:43:26Z |
| publishDate | 2016-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-844f2f24122741e2a43b89e3c0215c7e2022-12-22T01:48:28ZengElsevierCell Reports2211-12472016-11-011761646165610.1016/j.celrep.2016.10.008Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-JoiningYlli Doksani0Titia de Lange1Laboratory for Cell Biology and Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10065, USALaboratory for Cell Biology and Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10065, USAShelterin protects chromosome ends from the DNA damage response. Although the mechanism of telomere protection has been studied extensively, the fate of double-strand breaks (DSBs) inside telomeres is not known. Here, we report that telomere-internal FokI-induced DSBs activate ATM kinase-dependent signaling in S-phase but are well tolerated and repaired efficiently. Homologous recombination contributes to repair, leading to increased telomere length heterogeneity typical of the alternative lengthening of telomeres (ALT) pathway. Furthermore, cells accumulate extra chromosomal telomeric signals (ECTS), a second hallmark of ALT. Telomere-internal DSBs are also repaired by a PARP1- and Ligase3-dependent reaction, suggesting alternative non-homologous end-joining (alt-NHEJ), which relies on microhomology at DSBs. However, as resected telomere-internal DSBs have perfect homology, their PARP1/Lig3-dependent end-joining may be more akin to single strand break repair. We conclude that shelterin does not repress ATM kinase signaling or DSB repair at telomere-internal sites, thereby allowing DNA repair to maintain telomere integrity.http://www.sciencedirect.com/science/article/pii/S2211124716313948telomereend-protectiont-looprecombinationalt-NHEJPARP1 |
| spellingShingle | Ylli Doksani Titia de Lange Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining Cell Reports telomere end-protection t-loop recombination alt-NHEJ PARP1 |
| title | Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining |
| title_full | Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining |
| title_fullStr | Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining |
| title_full_unstemmed | Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining |
| title_short | Telomere-Internal Double-Strand Breaks Are Repaired by Homologous Recombination and PARP1/Lig3-Dependent End-Joining |
| title_sort | telomere internal double strand breaks are repaired by homologous recombination and parp1 lig3 dependent end joining |
| topic | telomere end-protection t-loop recombination alt-NHEJ PARP1 |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716313948 |
| work_keys_str_mv | AT yllidoksani telomereinternaldoublestrandbreaksarerepairedbyhomologousrecombinationandparp1lig3dependentendjoining AT titiadelange telomereinternaldoublestrandbreaksarerepairedbyhomologousrecombinationandparp1lig3dependentendjoining |