Academic journal article Genetics

Functional Impact of the H2A.Z Histone Variant during Meiosis in Saccharomyces Cerevisiae

Academic journal article Genetics

Functional Impact of the H2A.Z Histone Variant during Meiosis in Saccharomyces Cerevisiae

Article excerpt

SEXUAL reproduction relies on a specialized cell division, meiosis, which reduces chromosome ploidy by half and is usually accompanied by cell differentiation processes that culminate in the formation of gametes. The reduction in chromosome complement is achieved by two consecutive rounds of nuclear division preceded by a single round of DNA replication. Premeiotic S-phase is followed by a long prophase I in which, before the first meiotic division, homologous chromosomes (homologs) pair, synapse, and recombine. Meiotic recombination is initiated by programmed DNA double-strand breaks (DSBs) generated by the Spo11 protein and a cohort of regulatory factors (Keeney et al. 2014). During the repair of a subset of these meiotic DSBs, crossovers between homologs are formed, which are essential for correct distribution of chromosomes to the meiotic progeny. Alignment of homologous chromosomes (pairing) and the stabilization of these interactions by the synaptonemal complex (SC) (synapsis) influence meiotic recombination outcomes (Hunter 2015). These crucial meiotic events are monitored by the so-called meiotic recombination checkpoint (MRC), an evolutionarily conserved surveillance mechanism that senses defective synapsis and/or recombination and imposes a block or delay in meiotic cell progression providing time to fix the faulty process to prevent aberrant chromosome segregation. The meiotic checkpoint network also operates in unperturbed meiosis to ensure the proper sequential execution of events (MacQueen and Hochwagen 2011; Subramanian and Hochwagen 2014).

In this work, we have used the zip1 mutant of the budding yeast Saccharomyces cerevisiae as a genetic tool to activate the MRC. Zip1 is a major structural component of the SC central region and ZIPl deletion impairs synapsis and crossover (CO) recombination (Dong and Roeder 2000; Borner et al. 2004; Voelkel-Meiman et al. 2015); as a consequence, the zip1 mutant experiences a significant MRC-dependent delay in the prophase to meiosis I transition (Herruzo et al. 2016). The zip1 -induced defects are detected by the Mec1-Ddc2(ATR"ATRIP) complex, resulting in phosphorylation of the Hop1 checkpoint adaptor at several residues, including T318 (Carballo et al. 2008; Refolio et al. 2011; Penedos et al. 2015). The Hop1 protein is a component of the lateral elements of the SC; its abundance, dynamics, and phosphorylation state at chromosome axes in response to checkpoint activation are finely tuned by the AAA+ ATPase Pch2 (Herruzo et al. 2016). Phosphorylated Hop1 recruits the meiosis-specific Mek1 protein to chromosomes facilitating the activation of this Rad53/ Chk2-related kinase containing an FHA domain in two steps: first by Mec1 -dependent phosphorylation and subsequently by in trans autophosphorylation of Mek1 dimers on its activation loop (Niu et al. 2005; Ontoso et al. 2013). In turn, active Mek1 stabilizes Hop1-T318 phosphorylation at chromosomes (Chuang et al. 2012). Mek1 promotes interhomolog recombination bias by the direct phosphorylation of the recombination mediator Rad54 at T154 to attenuate its interaction with the strand-exchange Rad51 protein (Niu et al. 2009). Also, the phosphorylation of Hed1 at Thr40 stabilizes this protein stimulating its inhibitory action on Rad51 (Callender et al. 2016). Mek1 also exerts a spatial control on recombination bias by a synapsis-dependent mechanism involving Pch2 (Subramanian et al. 2016). In addition, Mek1 is essential for the meiotic checkpoint response to the accumulation of unrepaired DSBs and to the zip1 -induced synapsis and/or recombination defects (Xu et al. 1997; Ontoso et al. 2013; Prugar et al. 2017). The arrest or delay at meiotic prophase I imposed by the MRC is established by two interconnected mechanisms: downregulation of the Ndt80 transcription factor and inhibitory phosphorylation of Cdc28CDK1 (Subramanian and Hochwagen 2014). Ndt80 is a master regulator of yeast meiotic development that activates the transcription of a number of genes involved in meiotic divisions and spore formation (Winter 2012). …

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