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

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

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Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
Institut de Biologie Physico-Chimique, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes CNRS, Sorbonne Universités, UPMC, Univ Paris 06, 75005 Paris, France.
Department of Molecular Microbiology and Biotechnology, Tel Aviv University, 69978 Tel Aviv, Israel.
Institute of Molecular Biology (IMB), 55128 Mainz, Germany; Faculty of Biology, Institute of Developmental Biology and Neurobiology, Johannes Gutenberg University Mainz, 55099 Mainz, Germany. Electronic address:


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.


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

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