Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle

Cell. 2017 Jun 29;170(1):72-85.e14. doi: 10.1016/j.cell.2017.06.006.


Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively. Consequently, the coordination of TERRA degradation with telomere replication is altered at shortened telomeres. R-loop persistence at short telomeres contributes to activation of the DNA damage response (DDR) and promotes recruitment of the Rad51 recombinase. Thus, the telomere length-dependent regulation of TERRA and TERRA R-loops is a critical determinant of the rate of replicative senescence.

Keywords: DDR; R-loop; RNA-DNA hybrid; RNase H2; Rat1; Rif2; TERRA; senescence; telomere.

MeSH terms

  • Cell Cycle*
  • Cellular Senescence
  • DNA Damage
  • Exoribonucleases / metabolism
  • Nucleic Acid Hybridization
  • Recombinational DNA Repair
  • Repressor Proteins / metabolism
  • Saccharomyces cerevisiae / cytology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Telomere / chemistry
  • Telomere / metabolism*
  • Telomere-Binding Proteins / metabolism


  • RIF2 protein, S cerevisiae
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Telomere-Binding Proteins
  • RIF1 protein, S cerevisiae
  • RAT1 protein, S cerevisiae
  • Exoribonucleases