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.
Highlights
Members of the conserved ATM/ATR family proteins are multi-functional serine/threonine kinases involved in a wide range of processes, including genome duplication, DNA damage repair, cell cycle progression, checkpoint regulation, and meiosis [1,2,3]
Of the eight SQ/TQ motifs, the phospho-threonine 318 (T318) is required for the essential recruitment and activation of Mek1, while the threonine at position 181 might play a different role [6]
Cytological analysis showed that both the α-pS298 and α-pT318 antibodies generated signals in nuclear spread samples prepared from a WT control and that these signals co-localized with α-Hop1 foci (Fig 1B and 1C)
Summary
Members of the conserved ATM/ATR family proteins are multi-functional serine/threonine kinases involved in a wide range of processes, including genome duplication, DNA damage repair, cell cycle progression, checkpoint regulation, and meiosis [1,2,3]. In response to most forms of DNA damage, Tel and Mec, the budding yeast ATM and ATR, utilize Rad (53BP1) and Rad (CHK2) as an adaptor and effector kinase, respectively [8, 9]. Tel1/Mec utilize Hop, a conserved meiotic chromosome axis protein, and Mek, a chromosome associated serine/threonine kinase, as a meiosisspecific adaptor and effector kinase, respectively [6, 11,12,13]
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