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

Graf, M., Bonetti, D., Lockhart, A., Serhal, K., Kellner, V., Maicher, A., et al. (2017). Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle. CELL, 170(1), 72-85.e14 [10.1016/j.cell.2017.06.006].

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

BONETTI, DIEGO
Co-primo
;
2017

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
Articolo in rivista - Articolo scientifico
DDR; R-loop; Rat1; Rif2; RNA-DNA hybrid; RNase H2; senescence; telomere; TERRA; Cell Aging; DNA Damage; Exoribonucleases; Nucleic Acid Hybridization; Recombinational DNA Repair; Repressor Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Telomere; Telomere-Binding Proteins; Cell Cycle; Biochemistry, Genetics and Molecular Biology (all)
English
2017
170
1
72
85.e14
partially_open
Graf, M., Bonetti, D., Lockhart, A., Serhal, K., Kellner, V., Maicher, A., et al. (2017). Telomere Length Determines TERRA and R-Loop Regulation through the Cell Cycle. CELL, 170(1), 72-85.e14 [10.1016/j.cell.2017.06.006].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/174226
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