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

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 (kd) 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 FRAP-ATM-TRAPP domain of Tel1 and 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.

Exo1 cooperates with Tel1/ATM in promoting recombination events at DNA replication forks

“…Since the kinase activity of Tel1 is essential only for some of the Tel1 functions, 23 , 25 , 27 , 45 , 52 , 53 , 54 , 55 , 56 but tel1Δ exo1Δ and tel1-kd exo1Δ cells show the same hypersensitivities to CPT, MMS, and HU ( Figure 1 A), we investigated how Exo1 supports the viability of tel1-kd cells. Furthermore, we focused on CPT treatment, because the lack of Exo1 and Tel1 activity strongly enhance the hypersensitivity to this agent.…”

To Fix or Not to Fix: Maintenance of Chromosome Ends Versus Repair of DNA Double-Strand Breaks

“…As Tel1 promotes ssDNA generation at both DSBs and telomeres [ 141 ], the delayed senescence in Tel1-deficient telomerase-negative cells can be due to a reduced amount of telomeric ssDNA. By studying the senescence phenotype of telomerase-deficient cells lacking Tel1 or expressing the hyperactive Tel1-hy184 mutant variant, which has been identified because of its ability to compensate for the lack of Mec1 function [ 142 ], it was shown that Tel1-hy184 anticipates senescence, while the lack of Tel1 or of its kinase activity delays it [ 143 ]. Neither Tel1-hy184 nor Tel1 kinase defective variant affects the generation of ssDNA at telomeres, suggesting that Tel1 function in promoting senescence is not directly linked to ssDNA generation.…”

Origin, Regulation, and Fitness Effect of Chromosomal Rearrangements in the Yeast Saccharomyces cerevisiae

“…In S. cerevisiae , Mec1-Ddc2 (orthologues of human ATR-ATRIP) and Tel1 (orthologue of human ATM) are two sensor kinases to perceive DSBs [ 70 ]. Mec1-Ddc2 senses ssDNA through interaction with RPA [ 71 ], while Tel1 is recruited to DSBs and activated by the MRX complex [ 72 ]. It was found that the mec1 tel1 null mutant showed a great increase (~13000 fold) in chromosomal rearrangement, of which most are chromosome translocations [ 73 , 74 ].…”