Telomere fusions and translocations: a bridge too far?
Graphical abstract
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)
- et al.
Resolving roadblocks to telomere replication
Methods Mol Biol
(2019) - et al.
BLM and SLX4 play opposing roles in recombination-dependent replication at human telomeres
EMBO J
(2017) - et al.
FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres
Proc Natl Acad Sci U S A
(2017) - et al.
Reconstitution of anaphase DNA bridge recognition and disjunction
Nat Struct Mol Biol
(2018) - et al.
A new class of ultrafine anaphase bridges generated by homologous recombination
Cell Cycle
(2018) Shelterin-mediated telomere protection
Annu Rev Genet
(2018)- et al.
Removal of shelterin reveals the telomere end-protection problem
Science
(2012) - et al.
TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions
Nat Commun
(2016) - et al.
Resolution of telomere associations by TRF1 cleavage in mouse embryonic stem cells
Mol Biol Cell
(2014) - et al.
Both the classical and alternative non-homologous end joining pathways contribute to the fusion of drastically shortened telomeres induced by TRF2 overexpression
Cell Cycle
(2019)