Deregulated telomere transcription causes replication-dependent telomere shortening and promotes cellular senescence

Abstract

Telomeres are transcribed into non-coding TElomeric Repeat containing RNAs (TERRA). We have employed a transcriptionally inducible telomere to investigate how telomere transcription affects telomere function in Saccharomyces cerevisiae. We report that telomere shortening resulting from high levels of telomere transcription stems from a DNA replication-dependent loss of telomere tracts, which can occur independent of both telomerase inhibition and homologous recombination. We show that in order for telomere loss to occur, transcription must pass through the telomere tract itself producing a TERRA molecule. We demonstrate that increased telomere transcription of a single telomere leads to a premature cellular senescence in the absence of a telomere maintenance mechanism (telomerase and homology directed repair). Similar rapid senescence and telomere shortening are also seen in sir2Δ cells with compromised telomere maintenance, where TERRA levels are increased at natural telomeres. These data suggest that telomere transcription must be tightly controlled to prevent telomere loss and early onset senescence.

Telomeres and disease: Enter TERRA

“…Intriguingly, the telomere loss associated with tiTELs in yeast is additive with the shortening that occurs due to the inactivation of telomerase. 56 These data indicate that deregulated TERRA transcription at yeast tiTELs can shorten telomeres, at least to an extent, independent of telomerase inhibition. Furthermore, telomerase compensates for sequence loss at yeast tiTELs, despite increased TERRA levels.…”

“…56 Consistently, yeast cells without a telomere maintenance pathway that are deleted for SIR2, RIF1 or RIF2 also senesce rapidly, 56,63 possibly, as a consequence of abnormally high TERRA levels in these mutant cells. These data lead to the provocative notion that in the absence of telomere maintenance, cellular senescence can be manipulated through the differential regulation of TERRA transcription, which in turn can either promote or prevent telomere loss (Fig.…”

“…Furthermore, we will speculate cells. 56 It has been proposed that high rates of TERRA transcription (potentially through the formation of TERRA/DNA hybrids) may cause replication fork stalling and eventual DNA breaks that lead to rapid telomere loss events. This would be consistent with the observations that DNA replication and transcription collisions (the DNA/RNA hybrids) elsewhere in the genome also lead to DNA damage and breaks.…”

“…53 The idea of TERRAmediated telomerase inhibition has recently been challenged by in vivo assays making use of transcriptionally-inducible telomeres (tiTELs). [54][55][56] In telomerase positive human cells the induced transcription of a single telomere does not have an effect on the length of the telomere being transcribed nor does it affect the length of other natural telomeres within the cells. 54,55 Furthermore, neither telomerase activity nor the ability of telomerase to elongate the transcribing telomere are affected.…”

“…55 These results are different to what has been observed at tiTELs in yeast where they become shortened in a cis dependent manner. 52,56 This may be a result of organismal differences of telomere length homeostasis, however it may also be due to the differential levels of transcription achieved by the inducible promoters used in the respective systems. Intriguingly, the telomere loss associated with tiTELs in yeast is additive with the shortening that occurs due to the inactivation of telomerase.…”