Penedos, AR; (2012) Regulation of Hop1 Function by Mec1/Tel1 Phosphorylation. Doctoral thesis , UCL (University College London).

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Abstract

Meiotic recombination is initiated with the formation of double-strand breaks (DSBs), which can be repaired by inter-sister (IS) or inter-homologue (IH) recombination. In most organisms, recombination between homologous chromosomes (homologues) is required to ensure the correct reductional segregation during meiosis I (MI). In contrast to mitotic recombination, during meiosis recombination between homologues is favoured over that between sister chromatids. This preference is referred to as IH bias. Budding yeast Hop1 is an evolutionarily conserved meiotic chromosome axis phosphoprotein. It is required for three essential processes in meiosis: (i) catalysis of programmed meiotic DSBs, (ii) repair of DSBs via IH recombination, and (iii) activation of prophase I checkpoint. Following Spo11-catalysis of DSBs, Hop1 is phosphorylated by Mec1/Tel1 at three serine (S) or threonine (T) residues within its SQ/TQ Cluster Domain (SCD), a Mec1/Tel1 and ATR/ATM target motif. The Mec1/Tel1 phosphorylation of Hop1 promotes the recruitment and activation of the effector kinase Mek1, which, in turn, are required for IH bias and meiotic checkpoint. To better understand the molecular mechanism by which the Mec1/Tel1- phosporylation regulates Hop1 function, two alleles where either serine 298 or threonine 318 residues within Hop1’s SCD were mutated to a non-phosphorylatable alanine (A) were characterised. Whilst both alleles confer a dmc1∆ arrest-deficient phenotype, hop1-S298A mutant, unlike hop1-T318A, produces highly viable spores at low temperature. Further characterisation of these alleles suggests that T318 phosphorylation is required for efficient recruitment and initial activation of Mek1, essential for recombination, whilst S298 phosphorylation is necessary for the maintenance of Hop1-Mek1 interaction and hyperphosphorylation of Mek1, required for prophase checkpoint activation.

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