Telomeres progressively shorten at every round of DNA replication in the absence of telomerase. When they become critically short, telomeres trigger replicative senescence by activating a DNA damage response that is governed by the Mec1/ATR and Tel1/ATM protein kinases. While Mec1/ATR is known to block cell division when extended single-stranded DNA (ssDNA) accumulates at eroded telomeres, the molecular mechanism by which Tel1/ATM promotes senescence is still unclear. By characterizing a Tel1-hy184 mutant variant that compensates for the lack of Mec1 functions, we provide evidence that Tel1 promotes senescence by signaling to a Rad9-dependent checkpoint. Tel1-hy184 anticipates senescence onset in telomerase-negative cells, while the lack of Tel1 or the expression of a kinase defective Tel1 variant delays it. Both Tel1-hy184 and Tel1-kd do not alter ssDNA generation at telomeric DNA ends. Furthermore, Rad9 and only partially Mec1 are responsible for the precocious senescence promoted by Tel1-hy184. This precocious senescence is mainly caused by the F1751I, D1985N and E2133K amino acid substitutions, which are located in the FAT domain of Tel1 and that also increase Tel1 binding to DNA ends. Altogether, these results indicate that Tel1 induces replicative senescence by directly signaling dysfunctional telomeres to the checkpoint machinery

Menin, L., Colombo, C., Maestrini, G., Longhese, M., & Clerici, M. (2019). Tel1/ATM Signaling to the Checkpoint Contributes to Replicative Senescence in the Absence of Telomerase. GENETICS, 213(2), 411-429 [10.1534/genetics.119.302391].

Tel1/ATM Signaling to the Checkpoint Contributes to Replicative Senescence in the Absence of Telomerase

Menin, Luca
Primo
;
Colombo, Chiara Vittoria
Secondo
;
Longhese, Maria Pia
Co-ultimo
;
Clerici, Michela
Co-ultimo
2019

Abstract

Telomeres progressively shorten at every round of DNA replication in the absence of telomerase. When they become critically short, telomeres trigger replicative senescence by activating a DNA damage response that is governed by the Mec1/ATR and Tel1/ATM protein kinases. While Mec1/ATR is known to block cell division when extended single-stranded DNA (ssDNA) accumulates at eroded telomeres, the molecular mechanism by which Tel1/ATM promotes senescence is still unclear. By characterizing a Tel1-hy184 mutant variant that compensates for the lack of Mec1 functions, we provide evidence that Tel1 promotes senescence by signaling to a Rad9-dependent checkpoint. Tel1-hy184 anticipates senescence onset in telomerase-negative cells, while the lack of Tel1 or the expression of a kinase defective Tel1 variant delays it. Both Tel1-hy184 and Tel1-kd do not alter ssDNA generation at telomeric DNA ends. Furthermore, Rad9 and only partially Mec1 are responsible for the precocious senescence promoted by Tel1-hy184. This precocious senescence is mainly caused by the F1751I, D1985N and E2133K amino acid substitutions, which are located in the FAT domain of Tel1 and that also increase Tel1 binding to DNA ends. Altogether, these results indicate that Tel1 induces replicative senescence by directly signaling dysfunctional telomeres to the checkpoint machinery
No
Articolo in rivista - Articolo scientifico
Scientifica
Tel1; checkpoint; replicative senescence; telomere
English
Menin, L., Colombo, C., Maestrini, G., Longhese, M., & Clerici, M. (2019). Tel1/ATM Signaling to the Checkpoint Contributes to Replicative Senescence in the Absence of Telomerase. GENETICS, 213(2), 411-429 [10.1534/genetics.119.302391].
Menin, L; Colombo, C; Maestrini, G; Longhese, M; Clerici, M
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/241794
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