Protein kinase activity of Tel1p and Mec1p, two
            <i>Saccharomyces cerevisiae</i>
            proteins related to the human ATM protein kinase

Mallory, Julia C.; Petes, Thomas D.

doi:10.1073/pnas.250475697

Cited by 136 publications

(151 citation statements)

References 28 publications

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“…MEC1 Promotes Apoptosis in cdc13-1 Cells-Both MEC1 and TEL1 are yeast homologues of the human ATM kinase (24) and are involved in telomere maintenance (25,26,30). Our studies have shown that MEC1 deletion can dramatically reduce (from 52 to 8%) caspase activation and ROS production in cdc13-1 cells (Fig.…”

Section: Inactivation Of Cdc13p Triggers Apoptotic Signals Inmentioning

confidence: 61%

“…Signals in cdc13-1 Cells-The essential protein Mec1, an ATM-like kinase (24), is a checkpoint protein and is involved in telomere maintenance (25)(26)(27)(28). Its essential function can be separated from its checkpoint and telomere functions by deletion of Sml1p, which regulates the nucleotide pools (26, 28 -30).…”

Section: Mec1 Plays An Important Role In Mediating Apoptoticmentioning

confidence: 99%

“…Like Mec1p, Tel1p is another yeast ATM homologue (24). Tel1p is known to be involved in telomere maintenance and checkpoint (32,33).…”

Section: Mec1 Plays An Important Role In Mediating Apoptoticmentioning

confidence: 99%

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Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast

Qi¹,

Li²,

Kuo³

et al. 2003

Journal of Biological Chemistry

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Inactivation of the budding yeast telomere binding protein Cdc13 results in abnormal telomeres (exposed long G-strands) and activation of the DNA damage checkpoint. In the current study, we show that inactivation of Cdc13p induces apoptotic signals in yeast, as evidenced by caspase activation, increased reactive oxygen species production, and flipping of phosphatidylserine in the cytoplasmic membrane. These apoptotic signals were suppressed in a mitochondrial ( o ) mutant. Moreover, mitochondrial proteins (e.g. MTCO3) were identified as multicopy suppressors of cdc13-1, suggesting the involvement of mitochondrial functions in telomere-initiated apoptotic signaling. These telomereinitiated apoptotic signals were also shown to depend on MEC1, but not TEL1, and were antagonized by MRE11. Our results are consistent with a model in which single-stranded G-tails in the cdc13-1 mutant trigger MEC1-dependent apoptotic signaling in yeast.Cdc13p is a budding yeast telomere binding protein (1-3). Cdc13p appears to be a multifunctional protein involved in both telomere replication and protection (1-4). Its role in telomere replication has been suggested based on the findings that it interacts with the catalytic subunit of DNA polymerase ␣ and an essential subunit of telomerase, Est1p (4), and a mutation form of CDC13, cdc13-2, shows the telomerase negative phenotype (3). Its essential role in protecting yeast telomeres is presumably related to its binding to the exposed G-strand (1-3, 5). Cdc13-1p (P371S), a temperature-sensitive mutant form of Cdc13p, is unable to protect telomeres at the restrictive temperature (1). At the non-permissive temperature, cells with the cdc13-1 allele exhibit extensive degradation of telomeres from the 5Ј-ends, the C-rich strands (C-strands). The C-strand degradation results in long single-stranded Gtails (up to 20 kb) at the 3Ј-ends. The abnormal telomeres in cdc13-1 at the non-permissive temperature lead to RAD9-dependent cell cycle arrest at the G 2 /M phase, as well as cell death (1, 6). However, the mechanism of cell death triggered by Cdc13p inactivation is unclear. It was assumed that essential gene deletion because of the C-strand degradation is the cause of the cell death.Yeast apoptosis is not well understood. Bax, Bcl-2, and other established apoptotic proteins have not been found in yeast cells. However, expression of human BAX in yeast induces cell death (7,8), accompanied by mitochondrial alkalinization and cytosol acidification (9). This process can be blocked by coexpression of human anti-apoptosis protein Bcl-2 (8). Additionally, aged mother cells and H 2 O 2 -treated cells have shown apoptosis markers in yeast, including flipping of phosphatidylserine (PS) 1 from the inner leaflet to the outer leaflet of the cytoplasmic membrane, DNA damage (by TUNEL assay), and reactive oxygen species (ROS) induction (10, 11). More recently, a caspase-like protease Yca1p has been identified in yeast and was found to regulate yeast cell death induced by H 2 O 2 treatment (12). Moreover, a bro...

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Section: Inactivation Of Cdc13p Triggers Apoptotic Signals Inmentioning

confidence: 61%

Section: Mec1 Plays An Important Role In Mediating Apoptoticmentioning

confidence: 99%

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Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast

Qi¹,

Li²,

Kuo³

et al. 2003

Journal of Biological Chemistry

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“…In Saccharomyces cerevisiae, cells lacking the two ATM-like kinases, TEL1 and MEC1, do not maintain telomere length (Craven and Petes, 1999;Ritchie et al, 1999) and undergo senescence similar to that observed in telomerase-deficient cells, despite having functional telomerase components (Chan et al, 2001). Furthermore, telomerase activation requires the ATM kinase functions of either TEL1 or MEC1 in humans, S. cerevisiae, and Schizosaccharomyces pombe (Vaziri, 1997;Naito et al, 1998;Ritchie et al, 1999;Mallory and Petes, 2000;Chan et al, 2001). This implies that ATM kinases positively regulate telomerase activity either directly or indirectly.…”

Section: Introductionmentioning

confidence: 98%

MEC3,MEC1,andDDC2Are Essential Components of a Telomere Checkpoint Pathway Required for Cell Cycle Arrest during Senescence inSaccharomyces cerevisiae

Enomoto

Glowczewski

Berman

2002

MBoC

119

146

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When telomerase is absent and/or telomeres become critically short, cells undergo a progressive decline in viability termed senescence. The telomere checkpoint model predicts that cells will respond to a damaged or critically short telomere by transiently arresting and activating repair of the telomere. We examined the senescence of telomerase-deficient Saccharomyces cerevisiae at the cellular level to ask if the loss of telomerase activity triggers a checkpoint response. As telomerasedeficient mutants were serially subcultured, cells exhibited a progressive decline in average growth rate and an increase in the number of cells delayed in the G2/M stage of the cell cycle. MEC3, MEC1, and DDC2, genes important for the DNA damage checkpoint response, were required for the cell cycle delay in telomerase-deficient cells. In contrast, TEL1, RAD9, and RAD53, genes also required for the DNA damage checkpoint response, were not required for the G2/M delay in telomerase-deficient cells. We propose that the telomere checkpoint is distinct from the DNA damage checkpoint and requires a specific set of gene products to delay the cell cycle and presumably to activate telomerase and/or other telomere repair activities. INTRODUCTIONTelomeres, the nucleotide-protein structures at the ends of linear chromosomes, serve as a cap to protect the ends of chromosomes (reviewed in Blackburn, 2000). The function of this cap must strike a balance between facilitating and limiting access to the telomere. The cap must allow access to telomeric DNA for DNA replication enzymes, replication forks, and telomerase. In contrast, access to other factors that degrade and/or modify DNA ends must be limited. Thus, the cap must be dynamic, coordinating access to telomere DNA with other cellular events such as DNA replication or mitosis.Telomere DNA is normally replicated by telomerase, a specialized reverse transcriptase that utilizes an RNA template that is an integral component of the enzyme. Telomerase is activated late in S phase, around the time when telomeres are replicated (Wellinger et al., 1993a(Wellinger et al., , 1993b. Cells that are telomerase-deficient due to mutations in the catalytic component of the enzyme, the template RNA, or other required factors undergo senescence, a progressive loss of viability that is dependent on the number of divisions after loss of telomerase (Lundblad and Szostak, 1989;McEachern and Blackburn, 1996;Nakamura et al., 1997). During senescence, telomeres become progressively shorter as population viability declines (Singer and Gottschling, 1994;Lendvay et al., 1996;McEachern and Blackburn, 1996;Lingner et al., 1997). In yeasts, senescence can be detected as reduced numbers of colony-forming units and decreased colony size on solid media or as a decline in the average culture growth rate in liquid cultures (Singer and Gottschling, 1994;Lendvay et al., 1996;McEachern and Blackburn, 1996;.Changes in telomere structure can cause cellular abnormalities. In human cells, overexpression of a dominantnegative form of TR...

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“…MEC1 serves as the master signal transducer of all checkpoints of the DDR by activating a signaling network for cell cycle arrest, DNA repair, and cell recovery (15). The major DNA damage checkpoint is at the G 2 /M stage of the cell cycle and this is effected by phosphorylation of Rad9 by Mec1 and activation of downstream effector kinases Chk1 and Rad53 (17)(18)(19). Transient cell cycle arrest at the G 2 /M checkpoint is brought about by stabilization of Pds1/securin through Chk1 and Rad53 (17).…”

mentioning

confidence: 99%

DNA Damage Response-mediated Degradation of Ho Endonuclease via the Ubiquitin System Involves Its Nuclear Export

Kaplun

Ivantsiv

Bakhrat

et al. 2003

Journal of Biological Chemistry

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Yeast mating switch Ho endonuclease is rapidly degraded by the ubiquitin system and this depends on the DNA damage response functions, MEC1, RAD9, and CHK1. A PEST sequence marks Ho for degradation. Here we show that the novel F-box receptor, Ufo1, recruits phosphorylated Ho for degradation. Mutation of PEST residue threonine 225 stabilizes Ho, yet HoT225A still binds Ufo1 in vitro. Stable HoT225A accumulates within the nucleus, whereas HoT225E is degraded. Deletion of the nuclear exportin Msn5 traps native Ho in the nucleus and extends its half-life. These experiments suggest that Ho is degraded in the cytoplasm. In mec1 mutants stable Ho accumulates within the nucleus; Ho produced in mec1 cells does not bind Ufo1. Thus the MEC1 pathway has functions both in phosphorylation of Thr-225 for nuclear export and in additional phosphorylations for binding Ufo1. Cells with HO under its genomic promoter, but stabilized by deletion of the Msn5 exportin, proliferate, but are multibudded. These experiments elucidate some of the links between the DNA damage response and degradation of Ho by the ubiquitin system.

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Protein kinase activity of Tel1p and Mec1p, two Saccharomyces cerevisiae proteins related to the human ATM protein kinase

Cited by 136 publications

References 28 publications

Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast

Inactivation of Cdc13p TriggersMEC1-dependent Apoptotic Signals in Yeast

MEC3,MEC1,andDDC2Are Essential Components of a Telomere Checkpoint Pathway Required for Cell Cycle Arrest during Senescence inSaccharomyces cerevisiae

DNA Damage Response-mediated Degradation of Ho Endonuclease via the Ubiquitin System Involves Its Nuclear Export

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