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 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.
Laboratory for Cell Biology and Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: ylli.doksani@ifom.eu.
Ylli
Y
Doksani
Laboratory for Cell Biology and Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address: delange@rockefeller.edu.
Titia
T
de Lange
D000818:Animals; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D000072481:DNA Ligase ATP / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins / Q000378:metabolism*; D059767:Recombinational DNA Repair; D016196:S Phase; D015398:Signal Transduction; D016615:Telomere / Q000378:metabolism*
D000075223:Poly-ADP-Ribose Binding Proteins; D011065:Poly(ADP-ribose) Polymerases; D000072481:DNA Ligase ATP; C000618818:Lig3 protein, mouse
PARP1; alt-NHEJ; end-protection; recombination; t-loop; telomere