Journal
CELL
Volume 170, Issue 1, Pages 72-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.06.006
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Funding
- CancerTelSys in the E:med program of the German Federal Ministry of Education and Research (BMBF) [01ZX1302]
- Deutsche Forschungsgemeinschaft (DFG) Heisenberg Program [LU1709/2-1]
- German CellNetworks Cluster of Excellence [EXC81]
- HBIGS MSc/PhD fellowship
- European Research Council [ERC-2010-StG 260906-D-END]
- Mairie de Paris (Programme Emergences)
- Fondation pour la Recherche Medicale [FRM DEQ20160334914]
- Initiative d'Excellence program from the French State (grant DYNAMO) [ANR-11-LABX-0011-01]
- Lebanese National Council for Scientific Research
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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.
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