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Logo of mconcolMolecular & Cellular Oncology
Mol Cell Oncol. 2014 Jul-Sep; 1(3): e963438.
Published online 2014 October 29. doi:  10.4161/23723548.2014.963438
PMCID: PMC4904885

How do telomeres and NHEJ coexist?


The telomeres of eukaryotes are stable open double-strand ends that coexist with nonhomologous end joining (NHEJ), the repair pathway that directly ligates DNA ends generated by double-strand breaks. Since a single end-joining event between 2 telomeres generates a circular chromosome or an unstable dicentric chromosome, NHEJ must be prevented from acting on telomeres. Multiple mechanisms mediated by telomere factors act in synergy to achieve this inhibition.

Keywords: dicentric, KU, Lig4, Mre11, NHEJ, Rap1, telomere, TRF2


nonhomologous end joining

Telomeres Do Not Fuse

Telomeres are the DNA–protein complexes at the ends of linear chromosomes that solve the problem of replicating chromosome ends by semiconservative DNA replication. They also protect the native chromosome ends from the DNA repair pathways that act on ends generated by double-strand breaks. Evolution has solved this issue differently in prokaryotes and in eukaryotes. In several bacteria and viruses, linear chromosomes have covalently closed hairpin telomere ends. Replication produces inverted repeats that are processed into 2 covalently closed hairpins by a resolvase.1 In eukaryotes, telomeres are stable open double-strand ends and are therefore at risk of being erroneous substrates for DNA double-strand break repair.

Two pathways efficiently repair double-strand breaks: nonhomologous end joining (NHEJ) and homologous recombination.2-4 NHEJ is essentially direct relegation between the 2 ends. Homologous recombination is a more complex process that uses a template sequence for repair, most often the sister chromatid in mitotic cells. When these pathways act on telomeres, the consequences are quite different. Since telomeric DNA are tandem arrays of short duplex repeats in the same orientation relative to the chromosome ends, homologous recombination events between telomeres can elongate or shorten telomeres, but cannot fuse them. In other words, a recombination event at telomeres is without immediate consequence on chromosome structure and remains reversible as long as the telomere length stays above a minimum threshold. This length varies between organisms but seems remarkably short in all cases. Homologous recombination at telomeres is not fully repressed in normal cells and may play a physiological role in telomere length homeostasis, in particular when telomere length has shifted far from equilibrium or its usual range.5,6 In contrast, a single end-joining event mediated by NHEJ between 2 telomeres fuses them, generating either a dicentric chromosome or a circular chromosome, the latter being at risk of being converted into a dicentric through sister chromatid exchange. Dicentrics are unstable and can result in deleterious and potentially oncogenic copy number aberrations through several mechanisms such as breakage-fusion-bridge cycles, chromothrypsis, and polyploidization.7-11 Thus, the existence of a stable karyotype of linear chromosomes in all cells where the NHEJ pathway is active requires that NHEJ is fully prevented from acting on telomeres.12-16

It should be noted that chromosome end fusions can occur with or without telomeric sequences at the fusion. In the first case, telomere function failed despite the native sequence. How such telomere fusions with native telomere sequences are prevented is the topic of this review. In contrast, when all or most of the telomere repeats are missing, the fusion is a secondary consequence of telomere loss.15-18 In such cases, prevention of fusion relies on the mechanisms ensuring proper telomere sequence maintenance and replication, which will not be covered here.

The term NHEJ can refer to 2 distinct phenomena. The first is often called C-NHEJ (classic or canonical NHEJ) and is an efficient pathway in which a dedicated DNA ligase, LIG4, seals the double-strand ends. The second is often called A-NHEJ (alternative NHEJ). Here, very limited base pairing between single-strand 3′ tails allows ligation by LIG3 (the base excision repair ligase, absent in yeast) or eventual priming of DNA synthesis, the subsequent ligation being carried out by LIG1 (the main replicative ligase, ubiquitous in eukaryotes) but not LIG4. A-NHEJ is inhibited by replication protein A, and is mostly seen in circumstances where C-NHEJ and homologous recombination cannot act (e.g., in mutant contexts).3,19,20 A-NHEJ might be a back up for these normally efficient pathways or the accidental by-product of various activities acting on DNA in the nucleus, a sort of biochemical noise without a positive function in normal cells. In this review, the terms NHEJ and end joining will refer to LIG4-dependent C-NHEJ.

NHEJ is not always active. For example, it is transiently shut down during mitosis in mammals 21,22 and during S/G2 in the fission yeast Schizosaccharomyces pombe.23 In the budding yeast Saccharomyces cerevisiae, NHEJ is an haploid-specific pathway and is repressed in diploid cells.24-26 In the distantly related yeast Lachancea kluyveri, NHEJ was lost during evolution.27 The problem arising from the coexistence of telomeres and NHEJ is thus relieved in these contexts.

NHEJ Fails to Act on Telomere DNA Ends

The function of end joining is to reseal DNA ends formed by double-strand breaks.3 Its substrates are double-stranded ends that can be either blunt or possess short single-strand overhangs of a few nucleotides. DNA ends with short and perfectly cohesive overhangs can be repaired very efficiently and accurately by NHEJ. If nucleotides at the ends are damaged (e.g., at breaks generated by ionizing radiation), end joining can still process and repair the broken ends but the native sequences may not be restored. Repair is also slower and in some organisms inefficient.3 In most eukaryotes, telomeres are composed of an oriented G-rich repeated motif (e.g., TG1–3 in S. cerevisiae and TTAGGG in vertebrates). They are mostly double-stranded, but display a short terminal 3′ single-strand overhang of approximately 5–10 nt in budding yeast and 20–300 nt in vertebrates.28,29 Thus, 2 telomeres will not form short cohesive overhangs. If anything else, their fusion by NHEJ would be a relatively slow act involving extensive processing of the ends. This kinetic effect might be the first barrier against fusions with which other mechanisms synergize.

NHEJ acts on double-stranded ends, which are only transiently stable. If the ends remain unrepaired, several nuclease activities degrade the 5′ ends to generate single-strand 3′ tails that are no longer substrates for NHEJ2,3,30 but are instead committed to homologous recombination. Thus, it should be protective to maintain stable 3′ single-strand overhangs at telomeres that are long enough not to be a substrate for NHEJ. This maintenance results from a regulated equilibrium between 5′ degradation and DNA synthesis priming on the single-strand G-rich tails.31-35,102

In mammals, stability of the 5′ strand at the broken ends requires the recruitment of 53BP1 through a series of local histone modifications by ATM, RNF8, and RNF168.36 53BP1 protects 5′ ends through at least 2 effectors—RIF1 and PTIP—that either prevent 5′ degradation or reverse it through DNA synthesis.37-39 53BP1 is important for NHEJ events requiring relatively complex processing of the ends, in particular the fusions of ends from distinct breaks.39 The relative slowness of these reactions may explain why they strongly depend on the extensive 5′ stability established by 53BP1. Telomere fusions also require 53BP1.40 In normal cells, 53BP1 is excluded from telomeres.41,42 Thus, NHEJ inhibition at telomeres may in part rely on this exclusion.

53BP1 also helps to keep ends mobile. Whether this is a consequence of increased mobility of double-stranded ends versus single-stranded ends is unknown, but since distant ends must meet in order to be fused by NHEJ movement within the nucleus can be a key limiting step in telomere fusions.40 Through the exclusion of 53BP1, telomeres can attain a relative immobility that protects them against fusion. Similarly, excessive cohesion between sister telomeres favors their fusion by NHEJ.43

In addition to a simple 3′ single-strand overhang, the telomere DNA end may adopt unusual conformations to escape NHEJ. In one such case, the 3′ single-strand telomere end loops back to hybridize with the complementary strand of double-stranded telomere repeats, forming an intramolecular D-loop called the T-loop.44,45 This strand invasion reaction further engages the telomere end into a reversible homologous recombination intermediate. This shifts the issue from preventing NHEJ to preventing further commitment to homologous recombination (that is 3′ extension) and keeping this structure stable (a D-loop is normally transient and unfolded by helicases or cut by nucleases). A likely gain from this structure is that it is less problematic to proceed into a full homologous recombination event once in a while (causing only telomere elongation or shortening) than to generate a single telomere fusion. In other words, it seems best to chose the less harmful of 2 bad events. The 3′ telomere single-strand tails are also sufficiently G rich to form G-quadruplexes that could oppose NHEJ.46,47 The T-loop and G-quadruplex structures may also help to protect the 3′ telomere single-strand tails from A-NHEJ. In yeast, the 3′ telomere single-strand tails are probably too short to form stable T-loops or G-quadruplexes structures, but they may also be too short for A-NHEJ. Similarly, in Arabidopsis a large fraction of telomeres are blunt-ended and unlikely to adopt a secondary structure.48 In some species, including S. cerevisiae and ciliates, A-NHEJ is also prevented by the lack of base pairing between 3′ telomere overhangs.

NHEJ involves a 3 protein complexes containing KU, Mre11, and Lig4.3,49 KU is a DNA end-binding factor that encircles double-stranded DNA.50,51 An abundant protein, it binds very rapidly to the broken ends of a double-strand break. Whether more than one KU molecule binds to each end is unclear. At the minimum, the function of KU is to restrain 5′ resection and control the recruitment of Mre11 and Lig4.52,53 It probably also provides part of the scaffold that might align the ends and bring them in close proximity with the correct phasing to facilitate ligation by Lig4.54 Unfortunately, this is still speculative and we do not have a complete understanding of the roles of KU during the NHEJ process. The Mre11 complex is involved in several DNA repair processes, including NHEJ.49,55-57 This complex binds to double-stranded DNA ends and might help to tether the ends together58,59 As already mentioned, Lig4 is an ATP-dependent DNA ligase dedicated to NHEJ.53,60 The 2 Lig4 co-factors are Lif1 and Nej1 in budding yeast, and XRCC4 and XLF/CERNU in mammals.61 XRCC4-XLF can form polymers in vitro and may thus act as a splint bridging the 2 broken ends,62,63 a model that remains to be tested in vivo. In addition to these core factors, NHEJ can mobilize a DNA polymerase from the pol-X family to fill in short gaps at the ends prior to ligation: Pol4 in budding yeast; Pol λ and Pol μ in mammals.64,65 In budding yeast, most telomere fusions by NHEJ require Pol4.66

KU is normally present at telomeres, presumably bound to the telomere DNA end.67,68 Thus, inhibition of NHEJ at telomeres does not involve excluding KU from telomeres. As at double-strand breaks, one function of KU at telomeres is to limit 5′ resection, thus helping to set the size of the 3′ single-strand telomere overhang.29,33,67 In budding yeast, KU also helps to recruit telomerase and a heterochromatin factor, Sir4, at telomeres.69-71 In contrast to KU, the Mre11 complex, Lig4, and its co-factors are absent from telomeres.72,73 This indicates that NHEJ inhibition is in part based on their exclusion from telomeres, or at least their inability to form a stable complex with telomere DNA ends. An exception is during replication, when Mre11 can be transiently recruited to telomeres.74,75 At this time, Mre11 is important for telomere elongation by telomerase, at least in budding yeast where the bulk of elongation depends upon Mre11 and its associated checkpoint kinase Tel1ATM. In particular, Mre11 plays an important role in replication-coupled 5′ resection at telomeres, a key step in generating the 3′ single-stranded tails that telomerase can elongate.76,77 Thus, during telomere replication the inhibition of NHEJ must rely on mechanisms other than Mre11 exclusion.

Multiple Pathways Established by Telomere Factors Synergize to Inhibit NHEJ

The telomere repeated motifs allow the concentration of specialized proteins that recognize them and establish telomeric functions.78 Perhaps not surprisingly, proteins bound to the double-stranded telomeric repeats and the factors recruited by these proteins are essential to protect telomeres from NHEJ in all species in which this question has been addressed. In the fission yeast S. pombe, the Taz1 protein binds telomeric DNA and recruits the Rap1 protein. In the absence of Taz1 or Rap1, telomeres fuse together in a process that requires Lig4, KU, and Mre11.12,57,79 Thus, both Taz1 and Rap1 are required for NHEJ inhibition, but how these proteins function is unknown.

In mammals, 2 Taz1 orthologs, TRF1 and TRF2, bind double-stranded telomeric DNA. TRF2 also recruits RAP1 to telomeres. In the absence of TRF2, telomeres fuse extensively in a KU, LIG4, and MRE11-dependent manner indicating that TRF2 is essential for NHEJ inhibition.14,41,55,80,81 In cells lacking RAP1, telomere fusions remain below detection threshold.82 However, in cells where TRF2 is detached from telomeres, artificial tethering of RAP1 to the telomeres re-establishes NHEJ inhibition independently of TRF2.83 This suggests that TRF2 protects telomeres from NHEJ through multiple mechanisms, at least one of which involves RAP1 and the others being RAP1-independent. TRF1 also contributes to NHEJ inhibition, perhaps indirectly by favoring TRF2 assembly or function.84,85

Details of each inhibitory pathway established by TRF2 are starting to emerge. First TRF2, but not RAP1, is essential to exclude 53BP1 from telomeres through the synergistic inhibition of ATM and RNF168.42 TRF2 helps to maintain non-compact chromatin at telomeres that disfavors NHEJ.86 Inhibition of NHEJ by TRF2 in complex with RAP1 can be established in vitro on short double-stranded substrates, suggesting that the RAP1-dependent pathway is not related to a structure established by the 3′ telomere single-strand overhang.87 TRF2 also directly interacts with KU and this interaction might help to inhibit NHEJ by preventing a KU self-association that is predicted to bridge DNA ends during the NHEJ process.54 In addition, TRF2 protects telomeric 3′ single-strand overhangs from degradation by the nuclease activities of the XPF/ERCC1 and MRE11 complexes.88,89 TRF2 also generates T-loops independently of RAP1 in vitro and in vivo, in part through promotion of supercoiling and strand invasion and in part through protection of the Holliday junctions.45,90,91 It should be noted that T-loops were observed after psoralen crosslinking in isolated nuclei so it remains formally possible that their accumulation is a TRF2-dependent artifact generated during nuclei isolation and that such structures are transient and unfolded by helicases in living cells.

In S. cerevisiae, there is no ortholog of Taz1/TRF1/TRF2 and the Rap1 protein directly binds the telomere sequences at a density of approximately 15–20 molcules per telomere. In yeast cells lacking Rap1, the telomeres fuse in a KU, Lig4, and Mre11-dependent manner.92 Rap1 establishes at least 3 distinct pathways to inhibit NHEJ.93 One requires the Rap1-interacting factor Rif2, an AAA+ protein originating from a recent duplication of an ORC subunit gene in the yeast lineage. Two insights suggest the mode of action of Rif2. First, Rif2 inhibits NHEJ at a double-strand break in the absence of telomeric DNA when it is artificially targeted there by a domain of Rap1. This suggests that Rif2 acts on protein complexes and not through a telomere-specific DNA structure. It also shows that NHEJ inhibition by Rif2 is a standard cis effect in which the recruitment of a factor locally inhibits a molecular function. Second, Rif2 inhibits not only NHEJ at telomeres, but also all other Mre11-dependent processes (5′ resection, telomerase-mediated telomere elongation and a pathway of homologous recombination between telomeres).6,33,93-97 The simplest hypothesis is that Rif2 inhibits the Mre11 complex; this single molecular activity would explain the multifunctionality of Rif2. However, for now the mechanism of Rif2 remains unknown. The origin of Rif2 suggests that ORC may play a similar role at telomeres in other eukaryotes, for example in human cells where ORC is recruited to telomeres by TRF2.98

Independently of Rif2, in budding yeast Rap1 inhibits NHEJ at telomeres through recruitment of the heterochromatin factor Sir4, a yeast-specific protein of unknown evolutionary origin.93 Interestingly, Sir4 interacts directly with KU.69 This interaction is essential for stable Sir4 recruitment at telomeres but may also inhibit NHEJ, for example by disrupting the assembly of Lig4 on KU molecules bound to DNA ends.53 Although this scenario remains speculative, the parallel with the TRF2-KU interaction in mammals is striking. Interestingly, Sir4 directly interacts with DNA in vitro.99 Whether this property is related to NHEJ inhibition is unknown.

Rap1 in budding yeast also inhibits NHEJ independently of Rif2 and Sir4 through a region of the protein that includes its DNA binding domain.93 The same region also inhibits 5′ degradation and Mre11 recruitment.72 DNA binding by Rap1 may directly out-compete the stable assembly of Mre11 on DNA ends, favor a DNA secondary structure that is resistant to NHEJ and 5′ degradation, or recruit unidentified effectors.

We recently found that the yeast translocase and SUMO-dependent ubiquitin ligase Uls1 are essential to maintain NHEJ inhibition at telomeres.100 Uls1 does not act in a specific inhibitory pathway; instead, its role is to ensure that Rap1 function is maintained. Specifically, Uls1 eliminates rare non-functional poly-SUMOylated Rap1 molecules bound to telomeres. How poly-SUMOylation cripples the ability of Rap1 to inhibit NHEJ is unknown.

Thus, in both mammals and in yeast, multiple mechanisms cooperate to fully inhibit NHEJ at telomeres. Their synergy is reinforced by the multiplicity of DNA-bound molecules at each telomere and ensures that NHEJ inhibition at telomeres is continuously efficient and resilient to normal telomere length fluctuation. In budding yeast, the protection against telomere fusions goes one step further: dicentrics formed by telomere fusions often break at the fusions during mitosis, a process that restores the parental chromosomes.101 By allowing reversibility of telomere fusions, this rescue pathway can back up a temporary lapse of NHEJ inhibition at telomeres, further protecting the cell from the deleterious consequences of an unstable karyotype.


The author would like to thank Karine Dubrana, Madalena Tarsounas and Pablo Radicella for helpful criticism and advice on this review.


Studies in the author's laboratory are supported by grants from ARC and ANR (Blanc-SVSE-8-2011-TELO&DICENs).


1. Aihara H., Huang WM., Ellenberger T.. An interlocked dimer of the protelomerase TelK distorts DNA structure for the formation of hairpin telomeres. Mol Cell 2007; 27:901-13; PMID:17889664; [PMC free article] [PubMed] [Cross Ref]
2. Symington LS., Gautier J.. Double-strand break end resection and repair pathway choice. Annu Rev Genet 2011; 45:247-71; PMID:21910633; [PubMed] [Cross Ref]
3. Bétermier M., Bertrand P., Lopez BS.. Is non-homologous end-joining really an inherently error-prone process? Plos Genet 2014; 10:e1004086; PMID:24453986; [PMC free article] [PubMed] [Cross Ref]
4. Le Guen T., Ragu S., Guirouilh-Barbat J., Lopez BS. Role of the double-strand break repair pathway in the maintenance of genomic stability. Mol Cell Oncol 2014; in press.
5. Li B., Lustig AJ.. A novel mechanism for telomere size control in Saccharomyces cerevisiae. Genes Dev 1996; 10:1310-26; PMID:8647430; [PubMed] [Cross Ref]
6. Teixeira MT., Arneric M., Sperisen P., Lingner J.. Telomere length homeostasis is achieved via a switch between telomerase- extendible and -nonextendible states. Cell 2004; 117:323-35; PMID:15109493; [PubMed] [Cross Ref]
7. Stimpson KM., Song IY., Jauch A., Holtgreve-Grez H., Hayden KE., Bridger JM., Sullivan BA.. Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes. Plos Genet 2010; 6;PMID:20711355; [PMC free article] [PubMed] [Cross Ref]
8. Pampalona J., Frías C., Genescà A., Tusell L.. Progressive telomere dysfunction causes cytokinesis failure and leads to the accumulation of polyploid cells. Plos Genet 2012; 8:e1002679; PMID:22570622; [PMC free article] [PubMed] [Cross Ref]
9. Bunting SF., Nussenzweig A.. End-joining, translocations and cancer. Nat Rev Cancer 2013; 13:443-454; PMID:23760025; [PubMed] [Cross Ref]
10. Sorzano COS., Pascual-Montano A., Sánchez de Diego A., Martínez-A C., van Wely KHM.. Chromothripsis: breakage-fusion-bridge over and over again. Cell Cycle 2013; 12:2016-23; PMID:23759584; [PMC free article] [PubMed] [Cross Ref]
11. Li Y., Schwab C., Ryan SL., Papaemmanuil E., Robinson HM., Jacobs P., Moorman AV., Dyer S., Borrow J., Griffiths M, et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature 2014; 508:98-102; doi:10.1038/nature13115 [PMC free article] [PubMed] [Cross Ref]
12. Ferreira MG., Cooper JP.. The fission yeast Taz1 protein protects chromosomes from Ku-dependent end-to-end fusions. Mol Cell 2001; 7:55-63; PMID:11172711; [PubMed] [Cross Ref]
13. DuBois ML., Haimberger ZW., McIntosh MW., Gottschling DE.. A quantitative assay for telomere protection in Saccharomyces cerevisiae. Genetics 2002; 161:995-1013; PMID:12136006 [PubMed]
14. Smogorzewska A., Karlseder J., Holtgreve-Grez H., Jauch A., de Lange T.. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr Biol 2002; 12:1635-44; PMID:12361565; [PubMed] [Cross Ref]
15. Mieczkowski PA., Mieczkowska JO., Dominska M., Petes TD.. Genetic regulation of telomere-telomere fusions in the yeast Saccharomyces cerevisae. Proc Natl Acad Sci USA 2003; 100:10854-9; PMID:12963812 [PubMed]
16. Chan SW., Blackburn EH.. Telomerase and ATM/Tel1p protect telomeres from nonhomologous end joining. Mol Cell 2003; 11:1379-87; PMID:12769860; [PubMed] [Cross Ref]
17. Capper R., Britt-Compton B., Tankimanova M., Rowson J., Letsolo B., Man S., Haughton M., Baird DM.. The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev 2007; 21:2495-508; PMID:17908935; [PubMed] [Cross Ref]
18. Wang X., Baumann P.. Chromosome fusions following telomere loss are mediated by single-strand annealing. Mol Cell 2008; 31:463-73; PMID:18722173; [PubMed] [Cross Ref]
19. Sfeir A., de Lange T.. Removal of shelterin reveals the telomere end-protection problem. Science 2012; 336:593-7; PMID:22556254; [PMC free article] [PubMed] [Cross Ref]
20. Deng SK., Gibb B., de Almeida MJ., Greene EC., Symington LS.. RPA antagonizes microhomology-mediated repair of DNA double-strand breaks. Nat Struct Mol Biol 2014; 21:405-12; PMID:24608368; [PMC free article] [PubMed] [Cross Ref]
21. Lee D-H., Acharya SS., Kwon M., Drane P., Guan Y., Adelmant G., Kalev P., Shah J., Pellman D., Marto JA, et al. Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks. Mol Cell 2014; 54:512-25; PMID:24703952; [PMC free article] [PubMed] [Cross Ref]
22. Orthwein A., Fradet-Turcotte A., Noordermeer SM., Canny MD., Brun CM., Strecker J., Escribano-Diaz C., Durocher D.. Mitosis inhibits DNA double-strand break repair to guard against telomere fusions. Science 2014; 344:189-93; PMID:24652939; [PubMed] [Cross Ref]
23. Ferreira MG., Cooper JP.. Two modes of DNA double-strand break repair are reciprocally regulated through the fission yeast cell cycle. Genes Dev 2004; 18:2249-54; PMID:15371339; [PubMed] [Cross Ref]
24. Kegel A., Sjostrand JO., Astrom SU.. Nej1p, a cell type-specific regulator of nonhomologous end joining in yeast. Curr Biol 2001; 11:1611-7; PMID:11676923; [PubMed] [Cross Ref]
25. Valencia M., Bentele M., Vaze MB., Herrmann G., Kraus E., Lee SE., Schar P., Haber JE.. NEJ1 controls non-homologous end joining in Saccharomyces cerevisiae. Nature 2001; 414:666-9; PMID:11740566; [PubMed] [Cross Ref]
26. Frank-Vaillant M., Marcand S.. NHEJ regulation by mating type is exercised through a novel protein, Lif2p, essential to the ligase IV pathway. Genes Dev 2001; 15:3005-12; PMID:11711435; [PubMed] [Cross Ref]
27. Gordon JL., Byrne KP., Wolfe KH. Mechanisms of chromosome number evolution in yeast. Plos Genet 2011; 7:e1002190. [PMC free article] [PubMed]
28. Chow TT., Zhao Y., Mak SS., Shay JW., Wright WE.. Early and late steps in telomere overhang processing in normal human cells: the position of the final RNA primer drives telomere shortening. Genes Dev 2012; 26:1167-78; PMID:22661228; [PubMed] [Cross Ref]
29. Soudet J., Jolivet P., Teixeira MT.. Elucidation of the DNA end-replication problem in saccharomyces cerevisiae. Mol Cell 2014; 53:954-64; PMID:24656131; [PubMed] [Cross Ref]
30. Frank-Vaillant M., Marcand S.. Transient stability of DNA ends allows nonhomologous end joining to precede homologous recombination. Mol Cell 2002; 10:1189-99; PMID:12453425; [PubMed] [Cross Ref]
31. Lam YC., Akhter S., Gu P., Ye J., Poulet A., Giraud-Panis MJ., Bailey SM., Gilson E., Legerski RJ., Chang S.. SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair. EMBO J 2010; 29:2230-41; PMID:20551906; 10.1038/emboj.2010.58 [PubMed] [Cross Ref]
32. Wu P., van Overbeek M., Rooney S., de Lange T.. Apollo contributes to G overhang maintenance and protects leading-end telomeres. Mol Cell 2010; 39:606-17; PMID:20619712; [PMC free article] [PubMed] [Cross Ref]
33. Bonetti D., Clerici M., Anbalagan S., Martina M., Lucchini G., Longhese MP.. Shelterin-like proteins and Yku inhibit nucleolytic processing of Saccharomyces cerevisiae telomeres. Plos Genet 2010; 6:e1000966; PMID:20523746; [PMC free article] [PubMed] [Cross Ref]
34. Anbalagan S., Bonetti D., Lucchini G., Longhese MP.. Rif1 supports the function of the CST complex in yeast telomere capping. Plos Genet 2011; 7:e1002024; PMID:21437267; [PMC free article] [PubMed] [Cross Ref]
35. Wu P., Takai H., de Lange T.. Telomeric 3' overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 2012; 150:39-52; PMID:22748632; [PMC free article] [PubMed] [Cross Ref]
36. Aparicio T., Baer R., Gautier J.. DNA double-strand break repair pathway choice and cancer. DNA Repair (Amst) 2014; 19:169-75; PMID:24746645; [PMC free article] [PubMed] [Cross Ref]
37. Zimmermann M., Lottersberger F., Buonomo SB., Sfeir A., de Lange T.. 53BP1 regulates DSB repair using Rif1 to control 5' end resection. Science 2013; 339:700-4; PMID:23306437; [PMC free article] [PubMed] [Cross Ref]
38. Callen E., Di Virgilio M., Kruhlak MJ., Nieto-Soler M., Wong N., Chen H-T., Faryabi RB., Polato F., Santos M., Starnes LM, et al. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 2013; 153:1266-80; PMID:23727112; [PMC free article] [PubMed] [Cross Ref]
39. Zimmermann M., de Lange T.. 53BP1: pro choice in DNA repair. Trends Cell Biol 2014; 24:108-17; PMID:24094932; [PMC free article] [PubMed] [Cross Ref]
40. Dimitrova N., Chen Y-CM., Spector DL., de Lange T.. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature 2008; 456:524-8; PMID:18931659; [PMC free article] [PubMed] [Cross Ref]
41. Celli GB., de Lange T.. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat Cell Biol 2005; 7:712-8; PMID:15968270; [PubMed] [Cross Ref]
42. Okamoto K., Bartocci C., Ouzounov I., Diedrich JK., Yates JR., III, Denchi EL.. A two-step mechanism for TRF2-mediated chromosome-end protection. Nature 2013; 494:1-5; PMID:23389450; [PMC free article] [PubMed] [Cross Ref]
43. Hsiao SJ., Smith S.. Sister telomeres rendered dysfunctional by persistent cohesion are fused by NHEJ. J Cell Biol 2009; 184:515-26; PMID:19221198; [PMC free article] [PubMed] [Cross Ref]
44. Griffith JD., Comeau L., Rosenfield S., Stansel RM., Bianchi A., Moss H., de Lange T.. Mammalian telomeres end in a large duplex loop. Cell 1999; 97:503-14; PMID:10338214; [PubMed] [Cross Ref]
45. Doksani Y., Wu JY., de Lange T., Zhuang X.. Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell 2013; 155:345-56; PMID:24120135; [PMC free article] [PubMed] [Cross Ref]
46. Smith JS., Chen Q., Yatsunyk LA., Nicoludis JM., Garcia MS., Kranaster R., Balasubramanian S., Monchaud D., Teulade-Fichou M-P., Abramowitz L, et al. Rudimentary G-quadruplex-based telomere capping in Saccharomyces cerevisiae. Nat Struct Mol Biol 2011; 18:478-85; PMID:21399640; [PMC free article] [PubMed] [Cross Ref]
47. Tarsounas M., Tijsterman M.. Genomes and G-quadruplexes: for better or for worse. J Mol Biol 2013; 425:4782-9; PMID:24076189; [PubMed] [Cross Ref]
48. Kazda A., Zellinger B., Rössler M., Derboven E., Kusenda B., Riha K.. Chromosome end protection by blunt-ended telomeres. Genes Dev 2012; 26:1703-13; PMID:22810623; [PubMed] [Cross Ref]
49. Daley JM., Palmbos PL., Wu D., Wilson TE.. Nonhomologous end joining in yeast. Annu Rev Genet 2005; 39:431-51; PMID:16285867; [PubMed] [Cross Ref]
50. Walker JR., Corpina RA., Goldberg J.. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 2001; 412:607-14; PMID:11493912; [PubMed] [Cross Ref]
51. Grundy GJ., Moulding HA., Caldecott KW., Rulten SL.. One ring to bring them all–the role of Ku in mammalian non-homologous end joining. DNA Repair (Amst) 2014; 17:30-8; PMID:24680220; [PubMed] [Cross Ref]
52. Palmbos PL., Daley JM., Wilson TE.. Mutations of the Yku80 C terminus and Xrs2 FHA domain specifically block yeast nonhomologous end joining. Mol Cell Biol 2005; 25:10782-90; PMID:16314503; [PMC free article] [PubMed] [Cross Ref]
53. Palmbos PL., Wu D., Daley JM., Wilson TE.. Recruitment of saccharomyces cerevisiae Dnl4-Lif1 complex to a double-strand break requires interactions with Yku80 and the Xrs2 FHA domain. Genetics 2008; 180:1809-19; PMID:18832348; [PubMed] [Cross Ref]
54. Ribes-Zamora A., Indiviglio SM., Mihalek I., Williams CL., Bertuch AA.. TRF2 Interaction with Ku heterotetramerization interface gives insight into c-NHEJ prevention at human telomeres. Cell Rep 2013; 5:194-206; PMID:24095731; [PMC free article] [PubMed] [Cross Ref]
55. Deng Y., Guo X., Ferguson DO., Chang S.. Multiple roles for MRE11 at uncapped telomeres. Nature 2009; 460:914-8; PMID:19633651; [PMC free article] [PubMed] [Cross Ref]
56. Rass E., Grabarz A., Plo I., Gautier J., Bertrand P., Lopez BS.. Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nat Struct Mol Biol 2009; 16:819-24; PMID:19633668; [PubMed] [Cross Ref]
57. Reis CC., Batista S., Ferreira MG.. The fission yeast MRN complex tethers dysfunctional telomeres for NHEJ repair. EMBO J 2012; 31:4576-86; PMID:23188080; [PubMed] [Cross Ref]
58. Hohl M., Kwon Y., Galván SM., Xue X., Tous C., Aguilera A., Sung P., Petrini JHJ.. The Rad50 coiled-coil domain is indispensable for Mre11 complex functions. Nat Struct Mol Biol 2011; 18:1124-31; PMID:21892167; [PMC free article] [PubMed] [Cross Ref]
59. Deshpande RA., Williams GJ., Limbo O., Williams RS., Kuhnlein J., Lee J-H., Classen S., Guenther G., Russell P., Tainer JA, et al. ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling. EMBO J 2014; 33:482-500; PMID:24493214; [PubMed] [Cross Ref]
60. Chiruvella KK., Liang Z., Birkeland SR., Basrur V., Wilson TE.. Saccharomyces cerevisiae DNA ligase IV supports imprecise end joining independently of its catalytic activity. Plos Genet 2013; 9:e1003599; PMID:23825968; [PMC free article] [PubMed] [Cross Ref]
61. Callebaut I., Malivert L., Fischer A., Mornon JP., Revy P., de Villartay JP.. Cernunnos interacts with the XRCC4 x DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1. J Biol Chem 2006; 281:13857-60; PMID:16571728; [PubMed] [Cross Ref]
62. Ropars V., Drevet P., Legrand P., Baconnais S., Amram J., Faure G., Márquez JA., Piétrement O., Guerois R., Callebaut I, et al. Structural characterization of filaments formed by human Xrcc4-Cernunnos/XLF complex involved in nonhomologous DNA end-joining. Proc Natl Acad Sci USA 2011; 108:12663-8 [PubMed]
63. Ochi T., Wu Q., Blundell TL.. The spatial organization of non-homologous end joining: from bridging to end joining. DNA Repair (Amst) 2014; 17:98-109; PMID:24636752; [PMC free article] [PubMed] [Cross Ref]
64. Wilson TE., Lieber MR.. Efficient processing of DNA ends during yeast nonhomologous end joining. Evidence for a DNA polymerase beta (Pol4)-dependent pathway. J Biol Chem 1999; 274:23599-609; PMID:10438542; [PubMed] [Cross Ref]
65. Nick McElhinny SA., Havener JM., Garcia-Diaz M., Juarez R., Bebenek K., Kee BL., Blanco L., Kunkel TA., Ramsden DA.. A gradient of template dependence defines distinct biological roles for family x polymerases in nonhomologous end joining. Mol Cell 2005; 19:357-66; PMID:16061182; [PubMed] [Cross Ref]
66. Pardo B., Ma E., Marcand S.. Mismatch tolerance by DNA polymerase Pol4 in the course of nonhomologous end joining in saccharomyces cerevisiae. Genetics 2006; 172:2689-94; PMID:16452137; [PubMed] [Cross Ref]
67. Gravel S., Larrivee M., Labrecque P., Wellinger RJ.. Yeast Ku as a regulator of chromosomal DNA end structure. Science 1998; 280:741-4; PMID:9563951; [PubMed] [Cross Ref]
68. Wang Y., Ghosh G., Hendrickson EA.. Ku86 represses lethal telomere deletion events in human somatic cells. Proc Natl Acad Sci USA 2009; 106:12430-5; PMID:19581589; [PubMed] [Cross Ref]
69. Ribes-Zamora A., Mihalek I., Lichtarge O., Bertuch AA.. Distinct faces of the Ku heterodimer mediate DNA repair and telomeric functions. Nat Struct Mol Biol 2007; 14:301-7; PMID:17351632; [PubMed] [Cross Ref]
70. Pfingsten JS., Goodrich KJ., Taabazuing C., Ouenzar F., Chartrand P., Cech TR.. Mutually exclusive binding of telomerase RNA and DNA by Ku alters telomerase recruitment model. Cell 2012; 148:922-32; PMID:22365814; [PMC free article] [PubMed] [Cross Ref]
71. Williams JM., Ouenzar F., Lemon LD., Chartrand P., Bertuch AA.. The principal role of Ku in telomere length maintenance is promotion of Est1 association with telomeres. Genetics 2014; 197:1123-36; PMID:24879463 [PMC free article] [PubMed]
72. Negrini S., Ribaud V., Bianchi A., Shore D.. DNA breaks are masked by multiple Rap1 binding in yeast: implications for telomere capping and telomerase regulation. Genes Dev 2007; 21:292-302; PMID:17289918; [PubMed] [Cross Ref]
73. Fumagalli M., Rossiello F., Clerici M., Barozzi S., Cittaro D., Kaplunov JM., Bucci G., Dobreva M., Matti V., Beausejour CM, et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 2012; 14:355-65; PMID:22426077; [PMC free article] [PubMed] [Cross Ref]
74. Zhu XD., Kuster B., Mann M., Petrini JH., de Lange T.. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat Genet 2000; 25:347-52; PMID:10888888; [PubMed] [Cross Ref]
75. Takata H., Tanaka Y., Matsuura A.. Late S phase-specific recruitment of Mre11 complex triggers hierarchical assembly of telomere replication proteins in Saccharomyces cerevisiae. Mol Cell 2005; 17:573-83; PMID:15721260; [PubMed] [Cross Ref]
76. Larrivee M., LeBel C., Wellinger RJ.. The generation of proper constitutive G-tails on yeast telomeres is dependent on the MRX complex. Genes Dev 2004; 18:1391-6; PMID:15198981; [PubMed] [Cross Ref]
77. Faure V., Coulon S., Hardy J., Géli V.. Cdc13 and telomerase bind through different mechanisms at the lagging- and leading-strand telomeres. Mol Cell 2010; 38:842-52; PMID:20620955; [PubMed] [Cross Ref]
78. Shi T., Bunker RD., Mattarocci S., Ribeyre C., Faty M., Gut H., Scrima A., Rass U., Rubin SM., Shore D, et al. Rif1 and Rif2 Shape Telomere Function and Architecture through Multivalent Rap1 Interactions. Cell 2013; 153:1340-53; PMID:23746845; [PubMed] [Cross Ref]
79. Miller KM., Ferreira MG., Cooper JP.. Taz1, Rap1 and Rif1 act both interdependently and independently to maintain telomeres. EMBO J 2005; 24:3128-35; PMID:16096639; [PubMed] [Cross Ref]
80. van Steensel B., Smogorzewska A., de Lange T.. TRF2 protects human telomeres from end-to-end fusions. Cell 1998; 92:401-13; PMID:9476899; [PubMed] [Cross Ref]
81. Celli GB., Denchi EL., de Lange T.. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat Cell Biol 2006; 8:885-90; PMID:16845382; [PubMed] [Cross Ref]
82. Sfeir A., Kabir S., van Overbeek M., Celli GB., de Lange T.. Loss of Rap1 induces telomere recombination in the absence of NHEJ or a DNA damage signal. Science 2010; 327:1657-61; PMID:20339076; [PMC free article] [PubMed] [Cross Ref]
83. Sarthy J., Bae NS., Scrafford J., Baumann P.. Human RAP1 inhibits non-homologous end joining at telomeres. EMBO J 2009; 28:3390-9; PMID:19763083; [PubMed] [Cross Ref]
84. Sfeir A., Kosiyatrakul ST., Hockemeyer D., MacRae SL., Karlseder J., Schildkraut CL., de Lange T.. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 2009; 138:90-103; PMID:19596237; [PMC free article] [PubMed] [Cross Ref]
85. Martinez P., Thanasoula M., Munoz P., Liao C., Tejera A., McNees C., Flores JM., Fernandez-Capetillo O., Tarsounas M., Blasco MA.. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev 2009; 23:2060-75; PMID:19679647; [PubMed] [Cross Ref]
86. Bartocci C., Diedrich JK., Ouzounov I., Li J., Piunti A., Pasini D., Yates JR., III, Denchi EL. Isolation of chromatin from dysfunctional telomeres reveals an important role for ring1b in NHEJ-mediated chromosome fusions. Cell Rep 2014; 7:1320-1332; [PMC free article] [PubMed] [Cross Ref]
87. Bae NS., Baumann P.. A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Mol Cell 2007; 26:323-34; PMID:17499040; [PubMed] [Cross Ref]
88. Zhu XD., Niedernhofer L., Kuster B., Mann M., Hoeijmakers JH., de Lange T.. ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol Cell 2003; 12:1489-98; PMID:14690602; [PubMed] [Cross Ref]
89. Porro A., Feuerhahn S., Lingner J.. TERRA-reinforced association of LSD1 with MRE11 promotes processing of uncapped telomeres. Cell Rep 2014; 6:765-76; PMID:24529708; [PubMed] [Cross Ref]
90. Amiard S., Doudeau M., Pinte S., Poulet A., Lenain C., Faivre-Moskalenko C., Angelov D., Hug N., Vindigni A., Bouvet P, et al. A topological mechanism for TRF2-enhanced strand invasion. Nat Struct Mol Biol 2007; 14:147-54; PMID:17220898; [PubMed] [Cross Ref]
91. Poulet A., Buisson R., Faivre-Moskalenko C., Koelblen M., Amiard S., Montel F., Cuesta-Lopez S., Bornet O., Guerlesquin F., Godet T, et al. TRF2 promotes, remodels and protects telomeric holliday junctions. EMBO J 2009; 28:641-51; PMID:19197240; [PubMed] [Cross Ref]
92. Pardo B., Marcand S.. Rap1 prevents telomere fusions by nonhomologous end joining. EMBO J 2005; 24:3117-27; PMID:16096640; [PubMed] [Cross Ref]
93. Marcand S., Pardo B., Gratias A., Cahun S., Callebaut I.. Multiple pathways inhibit NHEJ at telomeres. Genes Dev 2008; 22:1153-8; PMID:18451106; [PubMed] [Cross Ref]
94. Wotton D., Shore D.. A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. Genes Dev 1997; 11:748-60; PMID:9087429; [PubMed] [Cross Ref]
95. Teng SC., Chang J., McCowan B., Zakian VA.. Telomerase-independent lengthening of yeast telomeres occurs by an abrupt Rad50p-dependent, Rif-inhibited recombinational process. Mol Cell 2000; 6:947-52; PMID:11090632; [PubMed] [Cross Ref]
96. Hirano Y., Fukunaga K., Sugimoto K.. Rif1 and rif2 inhibit localization of tel1 to DNA ends. Mol Cell 2009; 33:312-22; PMID:19217405; [PMC free article] [PubMed] [Cross Ref]
97. Ribeyre C., Shore D.. Anticheckpoint pathways at telomeres in yeast. Nat Struct Mol Biol 2012; 19:307-13; PMID:22343724; [PubMed] [Cross Ref]
98. Deng Z., Norseen J., Wiedmer A., Riethman H., Lieberman PM.. TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell 2009; 35:403-13; PMID:19716786; [PMC free article] [PubMed] [Cross Ref]
99. Kueng S., Tsai-Pflugfelder M., Oppikofer M., Ferreira HC., Roberts E., Tsai C., Roloff T-C., Sack R., Gasser SM.. Regulating repression: roles for the Sir4 N-Terminus in linker DNA protection and stabilization of Epigenetic States. Plos Genet 2012; 8:e1002727; PMID:22654676; [PMC free article] [PubMed] [Cross Ref]
100. Lescasse R., Pobiega S., Callebaut I., Marcand SEP.. End-joining inhibition at telomeres requires the translocase and polySUMO-dependent ubiquitin ligase Uls1. EMBO J 2013; 1-11; PMID:23211745; [PubMed] [Cross Ref]
101. Pobiega S., Marcand S.. Dicentric breakage at telomere fusions. Genes Dev 2010; 24:720-33; PMID:20360388; [PubMed] [Cross Ref]
102. Qi H., Zakian VA.. The Saccharomyces telomere-binding protein Cdc13p interacts with both the catalytic subunit of DNA polymerase alpha and the telomerase-associated est1 protein. Genes Dev 2000; 14:1777-88; PMID:10898792 [PubMed]

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