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Essential and Checkpoint Functions of Budding Yeast ATM and ATR during Meiotic Prophase Are Facilitated by Differential Phosphorylation of a Meiotic Adaptor Protein, Hop1.

Penedos A, Johnson AL, Strong E, Goldman AS, Carballo JA, Cha RS - PLoS ONE (2015)

Bottom Line: A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases.In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest.Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis.

View Article: PubMed Central - PubMed

Affiliation: Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, London, NW7 1AA, United Kingdom.

ABSTRACT
A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis.

No MeSH data available.


Related in: MedlinePlus

Model: Tel1/Mec1 phosphorylation of Hop1 at the T318 and S298 ensures effective coupling of meiotic recombination and progression.(i) Spo11-catalysis of meiotic DSBs triggers Tel1/Mec1 phosphorylation of chromosome bound Hop1 at multiple residues, including the T318 and S298. (ii) The phospho-T318 mediates the initial Mek1-recruitment and phosphorylation, independently of the phospho-S298. (iii) The phospho-S298 promotes stable Hop1-Mek1 interaction on chromosomes. (iv) The phospho-T318 and phospho-S298 promote spore viability by ensuring inter-homolog repair of meiotic breaks; available genetic evidence suggests that the phospho-T318 and phospho-S298 might be involved in regulating the Dmc1- and Rad51-dependent repair process, respectively (see text). (v) Once the essential crossover requirement is met, Ndt80 is activated, leading to exit from meiotic prophase (vi) and irreversible inactivation of Spo11-complex (vi). (viii) Hop1/Mek1 de-phosphorylation and removal from chromosomes ensue, accounting for the transient activation of the Hop1/Mek1-signalling during unchallenged meiosis. (ix, x) During challenged meiosis (e.g. dmc1Δ), Mek1 undergoes the Hop1 phospho-S298-dependent hyper-phosphorylation (ix), necessary for implementing a meiotic checkpoint response (x).
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pone.0134297.g005: Model: Tel1/Mec1 phosphorylation of Hop1 at the T318 and S298 ensures effective coupling of meiotic recombination and progression.(i) Spo11-catalysis of meiotic DSBs triggers Tel1/Mec1 phosphorylation of chromosome bound Hop1 at multiple residues, including the T318 and S298. (ii) The phospho-T318 mediates the initial Mek1-recruitment and phosphorylation, independently of the phospho-S298. (iii) The phospho-S298 promotes stable Hop1-Mek1 interaction on chromosomes. (iv) The phospho-T318 and phospho-S298 promote spore viability by ensuring inter-homolog repair of meiotic breaks; available genetic evidence suggests that the phospho-T318 and phospho-S298 might be involved in regulating the Dmc1- and Rad51-dependent repair process, respectively (see text). (v) Once the essential crossover requirement is met, Ndt80 is activated, leading to exit from meiotic prophase (vi) and irreversible inactivation of Spo11-complex (vi). (viii) Hop1/Mek1 de-phosphorylation and removal from chromosomes ensue, accounting for the transient activation of the Hop1/Mek1-signalling during unchallenged meiosis. (ix, x) During challenged meiosis (e.g. dmc1Δ), Mek1 undergoes the Hop1 phospho-S298-dependent hyper-phosphorylation (ix), necessary for implementing a meiotic checkpoint response (x).

Mentions: The evidence shown above indicates that the Tel1/Mec1 activation of Hop1/Mek1 proceeds in a stepwise manner dependent on the Hop1 phospho-T318 and phospho-S298: The phospho-T318 mediates essential Mek1 recruitment and phosphorylation (Fig 5ii) and the phospho-S298 promotes stable interaction between Hop1 and Mek1 on chromosomes, following the phospho-T318-dependent Mek1 recruitment (Fig 5iii). While both phospho-T318 and -S298 contribute to an essential function(s) of Hop1, our findings suggest that contribution of the phospho-S298 is minor compared to the essential Hop1 phospho-T318.


Essential and Checkpoint Functions of Budding Yeast ATM and ATR during Meiotic Prophase Are Facilitated by Differential Phosphorylation of a Meiotic Adaptor Protein, Hop1.

Penedos A, Johnson AL, Strong E, Goldman AS, Carballo JA, Cha RS - PLoS ONE (2015)

Model: Tel1/Mec1 phosphorylation of Hop1 at the T318 and S298 ensures effective coupling of meiotic recombination and progression.(i) Spo11-catalysis of meiotic DSBs triggers Tel1/Mec1 phosphorylation of chromosome bound Hop1 at multiple residues, including the T318 and S298. (ii) The phospho-T318 mediates the initial Mek1-recruitment and phosphorylation, independently of the phospho-S298. (iii) The phospho-S298 promotes stable Hop1-Mek1 interaction on chromosomes. (iv) The phospho-T318 and phospho-S298 promote spore viability by ensuring inter-homolog repair of meiotic breaks; available genetic evidence suggests that the phospho-T318 and phospho-S298 might be involved in regulating the Dmc1- and Rad51-dependent repair process, respectively (see text). (v) Once the essential crossover requirement is met, Ndt80 is activated, leading to exit from meiotic prophase (vi) and irreversible inactivation of Spo11-complex (vi). (viii) Hop1/Mek1 de-phosphorylation and removal from chromosomes ensue, accounting for the transient activation of the Hop1/Mek1-signalling during unchallenged meiosis. (ix, x) During challenged meiosis (e.g. dmc1Δ), Mek1 undergoes the Hop1 phospho-S298-dependent hyper-phosphorylation (ix), necessary for implementing a meiotic checkpoint response (x).
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Related In: Results  -  Collection

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pone.0134297.g005: Model: Tel1/Mec1 phosphorylation of Hop1 at the T318 and S298 ensures effective coupling of meiotic recombination and progression.(i) Spo11-catalysis of meiotic DSBs triggers Tel1/Mec1 phosphorylation of chromosome bound Hop1 at multiple residues, including the T318 and S298. (ii) The phospho-T318 mediates the initial Mek1-recruitment and phosphorylation, independently of the phospho-S298. (iii) The phospho-S298 promotes stable Hop1-Mek1 interaction on chromosomes. (iv) The phospho-T318 and phospho-S298 promote spore viability by ensuring inter-homolog repair of meiotic breaks; available genetic evidence suggests that the phospho-T318 and phospho-S298 might be involved in regulating the Dmc1- and Rad51-dependent repair process, respectively (see text). (v) Once the essential crossover requirement is met, Ndt80 is activated, leading to exit from meiotic prophase (vi) and irreversible inactivation of Spo11-complex (vi). (viii) Hop1/Mek1 de-phosphorylation and removal from chromosomes ensue, accounting for the transient activation of the Hop1/Mek1-signalling during unchallenged meiosis. (ix, x) During challenged meiosis (e.g. dmc1Δ), Mek1 undergoes the Hop1 phospho-S298-dependent hyper-phosphorylation (ix), necessary for implementing a meiotic checkpoint response (x).
Mentions: The evidence shown above indicates that the Tel1/Mec1 activation of Hop1/Mek1 proceeds in a stepwise manner dependent on the Hop1 phospho-T318 and phospho-S298: The phospho-T318 mediates essential Mek1 recruitment and phosphorylation (Fig 5ii) and the phospho-S298 promotes stable interaction between Hop1 and Mek1 on chromosomes, following the phospho-T318-dependent Mek1 recruitment (Fig 5iii). While both phospho-T318 and -S298 contribute to an essential function(s) of Hop1, our findings suggest that contribution of the phospho-S298 is minor compared to the essential Hop1 phospho-T318.

Bottom Line: A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases.In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest.Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis.

View Article: PubMed Central - PubMed

Affiliation: Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, London, NW7 1AA, United Kingdom.

ABSTRACT
A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis.

No MeSH data available.


Related in: MedlinePlus