Elevated levels of TRF2 induce telomeric ultrafine anaphase bridges and rapid telomere deletions

Abstract

The shelterin protein TRF2 is essential for chromosome-end protection. Depletion of TRF2 causes chromosome end-to-end fusions, initiating genomic instability that can be cancer promoting. Paradoxically, significant increased levels of TRF2 are observed in a subset of human cancers. Experimental overexpression of TRF2 has also been shown to induce telomere shortening, through an unknown mechanism. Here we report that TRF2 overexpression results in replication stalling in duplex telomeric repeat tracts and the subsequent formation of telomeric ultrafine anaphase bridges (UFBs), ultimately leading to stochastic loss of telomeric sequences. These TRF2 overexpression-induced telomere deletions generate chromosome fusions resembling those detected in human cancers and in mammalian cells containing critically shortened telomeres. Therefore, our findings have uncovered a second pathway by which altered TRF2 protein levels can induce end-to-end fusions. The observations also provide mechanistic insight into the molecular basis of genomic instability in tumour cells containing significantly increased TRF2 levels.

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…Specifically, we found Sun1 gene to be differentially expressed and observed an increase in TERF1 at fused telomeres. This is important as the recent paper showed that the increase in TERF1 leads to formation of chromosome fusions (111). Altogether our data support the notion that meiosis is transgenerationally affected.…”

The long and the short of TRF2 in neurogenesis

“…43 In addition, TRF2 overexpression promotes telomere shortening, an effect not caused by inhibition of telomerase 44 but instead by replication stalling in duplex telomeric regions and the formation of ultrafine anaphase bridges (UFBs), triggering chromosome fusions similar to those seen in human cancers. 45 Besides its function on telomeres, extra-telomeric functions of TRF2 have recently emerged. TRF2 is upregulated during human embryonic stem cell differentiation and promotes differentiation by binding to and preventing the proteasomal degradation of REST (Repressor ElementÀ1 Silencing Transcription Factor).…”

Knotty Problems during Mitosis: Mechanistic Insight into the Processing of Ultrafine DNA Bridges in Anaphase

“…1B) following exposure to aphidicolin Barefield and Karlseder 2012;d'Alcontres et al 2014). Interfering with the integrity of the shelterin complex via changing the levels of TRF1 or TRF2 also induces telomere fragility (Martinez et al 2009;Sfeir et al 2009) and gives rise to T-UFBs (d 'Alcontres et al 2014;Nera et al 2015). TRF1 was shown to protect against fragility by recruiting BLM to the telomeres (Sfeir et al 2009), suggesting that BLM facilitates replication (Drosopoulos et al 2015) or disentangles late-replicating structures at these regions Barefield and Karlseder 2012).…”