Homeostatic control of meiotic G2/prophase checkpoint function by Pch2 and Hop1

Abstract

Checkpoints cascades coordinate cell cycle progression with essential chromosomal processes. During meiotic G2/prophase, recombination and chromosome synapsis are monitored by what are considered distinct checkpoints [1-3]. In budding yeast, the AAA+ ATPase Pch2 is thought to specifically promote cell cycle delay in response to synapsis defects [4-6]. However, unperturbed pch2{Delta} cells are delayed in meiotic G2/prophase [6], suggesting paradoxical roles for Pch2 in cell cycle progression. Here, we provide insight into the checkpoint roles of Pch2 and its connection to Hop1, a HORMA domain-containing client protein. Contrary to current understanding, we find that the Pch2-Hop1 module is crucial for checkpoint function in response to both recombination and synapsis defects, thus revealing a shared meiotic checkpoint cascade. Meiotic checkpoint responses are transduced by DNA break-dependent phosphorylation of Hop1 [7, 8]. Based on our data and on the effect of Pch2 on HORMA topology [9-11], we propose that Pch2 promotes checkpoint proficiency by catalyzing the availability of signaling-competent Hop1. Conversely, we demonstrate that Pch2 can act as a checkpoint silencer, also in the face of persistent DNA repair defects. We establish a framework in which Pch2 and Hop1 form a homeostatic module that governs general meiotic checkpoint function. We show that this module can - depending on the cellular context - fuel or extinguish meiotic checkpoint function, which explains the contradictory roles of Pch2 in cell cycle control. Within the meiotic checkpoint, the Pch2-Hop1 module thus operates analogous to the Pch2/TRIP13-Mad2 module in the spindle assembly checkpoint that monitors chromosome segregation [12-16].