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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.

Author information

1
Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
2
Institut de Biologie Physico-Chimique, UMR8226, Laboratoire de Biologie Moléculaire et Cellulaire des Eucaryotes CNRS, Sorbonne Universités, UPMC, Univ Paris 06, 75005 Paris, France.
3
Department of Molecular Microbiology and Biotechnology, Tel Aviv University, 69978 Tel Aviv, Israel.
4
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: b.luke@imb-mainz.de.

Abstract

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

PMID:
28666126
DOI:
10.1016/j.cell.2017.06.006
[Indexed for MEDLINE]
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