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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.
Highlights
The shelterin protein TRF2 is essential for chromosome-end protection
TRF2 was found to be expressed at significantly higher levels in several breast cancer (MDA-MB-453, MDA-MB-468, ZR-75-1 and MCF-7) and melanoma cell lines (LOX, WM115, WM278, WM983A and WM1158) compared with the primary cells (IMR90, BJ and WI38) (Fig. 1a, Supplementary Fig. 1a), consistent with observations reported by other groups[23,33,34,35]
By examining the length of individual telomeres in cells overexpressing TRF2, we uncovered a subpopulation of termini that had undergone loss of almost the entire telomeric tract, which was often accompanied by end-to-end fusions
Summary
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. We report that TRF2 overexpression results in replication stalling in duplex telomeric repeat tracts and the subsequent formation of telomeric ultrafine anaphase bridges (UFBs), 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. The shelterin protein TRF2 has been reported to trigger telomere shortening by an unknown mechanism in a telomerase-independent manner[19,20,23,24]: overexpression of TRF2 can accelerate the rate of telomere erosion in human primary cells that do not have telomerase[20,24], and even trigger a DNA damage response[25] This suggests that TRF2 is involved in a telomere-processing function that is different from telomerase inhibition. Ultrafine anaphase bridges that are composed of telomeric sequences, are extremely rare, even when cells were challenged with replication inhibitors[28]
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