Abstract
Proper segregation of chromosomes during meiosis requires the formation and repair of double-strand breaks (DSBs) to form crossovers. Repair is biased toward using the homolog as a substrate rather than the sister chromatid. Pch2 is a conserved member of the AAA+-ATPase family of proteins and is implicated in a wide range of meiosis-specific processes including the recombination checkpoint, maturation of the chromosome axis, crossover control, and synapsis. We demonstrate a role for Pch2 in promoting and regulating interhomolog bias and the meiotic recombination checkpoint in response to unprocessed DSBs through the activation of axial proteins Hop1 and Mek1 in budding yeast. We show that Pch2 physically interacts with the putative BRCT repeats in the N-terminal region of Xrs2, a member of the MRX complex that acts at sites of unprocessed DSBs. Pch2, Xrs2, and the ATM ortholog Tel1 function in the same pathway leading to the phosphorylation of Hop1, independent of Rad17 and the ATR ortholog Mec1, which respond to the presence of single-stranded DNA. An N-terminal deletion of Xrs2 recapitulates the pch2Δ phenotypes for signaling unresected breaks. We propose that interaction with Xrs2 may enable Pch2 to remodel chromosome structure adjacent to the site of a DSB and thereby promote accessibility of Hop1 to the Tel1 kinase. In addition, Xrs2, like Pch2, is required for checkpoint-mediated delay conferred by the failure to synapse chromosomes.
Highlights
Meiosis is a specialized cell division program to produce haploid gametes
We found Pch2 functions with Tel1 and the MRX component Xrs2 to signal blunt-ended, unprocessed double-strand breaks (DSBs) intermediates of meiotic recombination
We propose that phosphorylation of the meiotic chromosome axis protein Hop1 depends on two partially redundant pathways: one pathway involving Tel1, Pch2 and Xrs2 that responds to the presence of unprocessed DSBs and another pathway involving Mec1 and Rad17 that responds to the presence of resected DSB intermediates of homologous recombination
Summary
Meiosis is a specialized cell division program to produce haploid gametes. To achieve faithful chromosome segregation during meiosis I (MI), cells utilize meiotic recombination to establish physical connections through the formation of chiasmata or crossing-over at the DNA level between homologous chromosomes [1].In budding yeast, meiotic recombination is initiated by programmed double-strand breaks (DSBs) catalyzed by a topoisomerase II-like enzyme Spo11 [2]. Meiosis is a specialized cell division program to produce haploid gametes. To achieve faithful chromosome segregation during meiosis I (MI), cells utilize meiotic recombination to establish physical connections through the formation of chiasmata or crossing-over at the DNA level between homologous chromosomes [1]. Meiotic recombination is initiated by programmed double-strand breaks (DSBs) catalyzed by a topoisomerase II-like enzyme Spo11 [2]. The 59 ends of DSBs are resected to produce 39 single-stranded DNA, at which Dmc and Rad load to mediate strand exchange with a homologous DNA sequence [3,4]. Unlike in vegetative cells where sister chromatids are preferred templates for DSB repair, most meiotic programmed DSBs are repaired using homologous non-sister chromatids [5,6,7]. CO formation and distribution is highly regulated during meiosis; each homolog must receive at least one CO to sustain reductional segregation in meiosis I [11]
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