Telomere fusions and translocations: a bridge too far?

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Telomere fusions inevitably arise as a cell’s last-ditch effort to protect exposed chromosomal ends when telomeres are lost due to aging-associated erosion, breakage, failed replication, or a plethora of other cellular mistakes. Fusion of an exposed chromosomal end to another telomere presumably presents a superficially attractive option to the cell as opposed to the alternative of the impending degradation of the unprotected chromosomal terminus. However, when allowed to progress to mitosis these fusion events subsequently foster non-disjunction or bridge:breakage events — both of which drive highly pathogenic genomic instability and additional chromosomal translocations. Thus, the question becomes how and when telomere fusion events arise and, most importantly, is there a mechanism available to resolve these telomere bridges such that proper repair, and not genomic instability, results? Recent evidence suggests that the formation, and then the resolution of, ultrafine bridges may facilitate this process.

Introduction

Functional telomeres are a critical feature of a stable genome (Figure 1a). Conversely, when telomeres become dysfunctional, telomere fusions and ultimately genomic instability or cellular death ensue. The first line of defense against telomere fusion events is proper telomeric capping, which is provided by a six-subunit telomere protection complex termed Shelterin [1]. The loss of Shelterin subunits via experimental intervention uniformly yields rampant telomere fusions in the absence of telomeric erosion [2,3]. In a complementary fashion, the overexpression of Telomere Recognition Factor 1 (TRF1) and Telomere Recognition Factor 2 (TRF2), which are key Shelterin subunits often frequently overexpressed in cancers, leads to similar telomere fusion outcomes [4,5]. Somewhat confusingly, germline mutations in Shelterin are often more associated with telomere attrition, not telomere fusion [1]. Nonetheless, it is clear that proper (i.e. not too little and not too much) Shelterin expression unequivocally promotes appropriate capping (Figure 1b). Perhaps the least abrupt form of telomere dysfunction induced by Shelterin loss lies in the gradual, global telomere shortening associated with aging [6]. Aged, shortened telomeres result perforce in reduced Shelterin occupancy. Consequently, cells — in the absence of functional checkpoints which should instead trigger senescence — harboring such telomeres have elevated frequencies of telomere sister fusions [7,8] and/or fusions associated with massive fragmentation (aka chromothripsis) [9] (Figure 1c). While it is intuitive that the aberrant conditions of dysfunctional Shelterin expression or advanced aging can cause telomere fusions it needs to be emphasized that these are infrequent conditions/situations. Indeed, Shelterin mutations arise in patient populations only very rarely although when they do occur they are associated with severe pathologies including Dyskeratosis Congenita [10]. Only recently has it also been appreciated that the safeguarding provided by Shelterin is transiently abrogated to permit passage of the replication fork and that this reduction in Shelterin protection probably provides the most frequent window of opportunity for the genesis of telomere catastrophe by way of stalled or failed replication (Figure 1d).

Section snippets

Replication-driven fusions

Telomeric DNA is notoriously difficult to replicate due to its repetitive (TTAGGG)n nature, fragile site categorization, and its tendency to form difficult-to-dismantle secondary structures. For example, the transient dissociation of Shelterin binding to telomeric DNA that is required to enable DNA replication also likely permits the formation of G-quadraplex (G4) structures that can stall the replication fork [11,12]. Thus, it becomes incumbent upon cells to be able to limit the frequency of

Telomere bridges

Regardless of the precise mechanism by which they occur, the above-listed events share a common feature – telomere shortening and dysfunction with a high propensity for the telomeres to fuse. Telomere sister chromatid fusion largely depends on DNA Ligase 1, while general intra- and interchromsomal translocations are more reliant on DNA Ligases 3 and 4 [8,31]. These aberrant repair events are, in turn, solely dependent on either alternative or classical NHEJ in a manner that is determined

Translocations resulting from broken UFBs

Unfortunately, not all UFBs are processed in a timely fashion and when telomeric UFB entities persist in mitosis, they require a break of some variety to resolve the bridge and yield two unfettered cells. This fusion > bridge > break order is equivalent to (and better known as) a breakage:fusion:bridge (BFB) cycle which may drive any number of telomere translocations in a given cell. Indeed, elevated UFBs derived from sister chromatid bridges have been associated with high levels of genomic

Funding

Work in the Hendrickson laboratory was supported in part by grants from the N.I.H. (GM088351) and the NCI (CA190492).

Conflict of interest statement

EAH is a member of the scientific advisory boards for Horizon Discovery and Intellia Therapeutics.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Dr. Duncan Baird for his laboratory’s long-standing contribution to our laboratory’s understanding of telomere dynamics. We thank Dr. Anja K. Bielinsky for her comments on the manuscript. S. S. prepared the original version of this manuscript as well as constructed all of the figures for it. E. A. H. helped with the editing of the manuscript.

References (49)

  • D.M. Baird et al.

    The extent and significance of telomere loss with age

    Ann N Y Acad Sci

    (2004)
  • K. Liddiard et al.

    Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4

    Genome Res

    (2016)
  • K. Liddiard et al.

    DNA Ligase 1 is an essential mediator of sister chromatid telomere fusions in G2 cell cycle phase

    Nucleic Acids Res

    (2019)
  • K. Cleal et al.

    Chromothripsis during telomere crisis is independent of NHEJ, and consistent with a replicative origin

    Genome Res

    (2019)
  • M. Jones et al.

    The shelterin complex and hematopoiesis

    J Clin Invest

    (2016)
  • A.L. Valton et al.

    G-quadruplexes in DNA replication: a problem or a necessity?

    Trends Genet

    (2016)
  • S. Stroik et al.

    CtIP is essential for telomere replication

    Nucleic Acids Res

    (2019)
  • F. Li et al.

    The BUB3-BUB1 complex promotes telomere DNA replication

    Mol Cell

    (2018)
  • R.E. Jones et al.

    Escape from telomere-driven crisis is DNA ligase III dependent

    Cell Rep

    (2014)
  • A.P. Sobinoff et al.

    Alternative lengthening of telomeres: DNA repair pathways converge

    Trends Genet

    (2017)
  • F. Li et al.

    ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization

    EMBO J

    (2019)
  • R. Hansel-Hertsch et al.

    G-quadruplex structures mark human regulatory chromatin

    Nat Genet

    (2016)
  • P. Margalef et al.

    Stabilization of reversed replication forks by telomerase drives telomere catastrophe

    Cell

    (2018)
  • A.M. Leon-Ortiz et al.

    A distinct class of genome rearrangements driven by heterologous recombination

    Mol Cell

    (2018)
  • Cited by (0)

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