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  • In S cerevisiae Mek a paralog of the checkpoint kinase

    2019-11-08

    In S. cerevisiae, Mek1, a paralog of the checkpoint kinase Chk2, mediates cell-cycle arrest in response to meiotic defects (Bailis and Roeder, 2000, Xu et al., 1997). Mek1 is associated with meiotic chromosome axes, where its activation requires interactions with two other axis proteins, Hop1 and Red1 (Niu et al., 2005, Niu et al., 2007). Hop1, a founding member of the HORMA (from Hop1, Rev7, and Mad2) domain family (Aravind and Koonin, 1998), is phosphorylated by ataxia telangiectasia mutated (ATM)/ATM- and RAD3-related (ATR)Mec1/Tel1 and serves as a meiosis-specific adaptor for Mek1 activation (Carballo et al., 2008). The mammalian HORMA domain proteins HORMAD1 and HORMAD2 localize along unsynapsed chromosome axes and recruit ATR to activate a meiotic checkpoint (Daniel et al., 2011, Shin et al., 2010, Wojtasz et al., 2012). Therefore, the chromosome axis provides a key interface for integrating meiotic chromosome dynamics and checkpoint signaling. However, how these proteins monitor chromosomal events and generate signals to regulate meiotic progression is unknown. In the nematode C. elegans, adult germlines contain a complete progression of meiotic stages in a spatiotemporal sequence (Figure 1A). The onset of meiotic prophase is marked by a dramatic change in nuclear morphology, in which the chromosome mass becomes asymmetrically distributed within the nucleus to form a crescent shape, defining the “transition zone” region of the germline. During this stage, special regions near one end of each chromosome, known as pairing centers (PCs), establish connections to microtubules through the nuclear envelope proteins SUN-1 and ZYG-12, which play essential roles in homolog pairing and synapsis, (Penkner et al., 2007, Sato et al., 2009). Through short sequence motifs enriched over several hundred kilobases, PCs recruit a family of zinc finger proteins essential for their functions: HIM-8, ZIM-1, ZIM-2, and ZIM-3 (Phillips and Dernburg, 2006, Phillips et al., 2005, Phillips et al., 2009). At least two kinases, PLK-2 and CHK-2, play central roles during early meiotic prophase in C. elegans. PLK-2 is one of three Polo-like kinases in C. elegans that are closely related to mammalian Plk1. PLK-1, which is essential for mitosis, can partially substitute for the function of PLK-2 in Almorexant (Harper et al., 2011, Labella et al., 2011). PLK-2 localizes to PCs upon meiotic entry, which leads to aggregation of SUN-1/ZYG-12 within the nuclear envelope, initiating dynein-driven chromosome motions that promote pairing and synapsis (Harper et al., 2011, Labella et al., 2011, Rog and Dernburg, 2015, Wynne et al., 2012). CHK-2 is a meiosis-specific paralog of Chk2 and is dispensable for the canonical DNA damage response (Higashitani et al., 2000, MacQueen and Villeneuve, 2001). Instead, CHK-2 governs two major pathways essential for crossover formation. It is required for nuclear reorganization leading to homolog pairing and synapsis and also for the programmed DSBs that initiate meiotic recombination (MacQueen and Villeneuve, 2001, Oishi et al., 2001). Upon meiotic entry, SUN-1 is phosphorylated at several sites in its nucleoplasmic domain, a subset of which requires PLK-2 and/or CHK-2 activity (Harper et al., 2011, Penkner et al., 2009). However, phosphorylation of the SUN-1 N terminus is largely dispensable for SUN-1/ZYG-12 aggregation and homolog pairing (Woglar et al., 2013). Therefore, the key targets of CHK-2 and PLK-2 that mediate pairing and synapsis remain to be identified. Recent studies have shown that CHK-2 is required for chromosomal localization of two DSB-promoting proteins, DSB-1 and DSB-2 (Rosu et al., 2013, Stamper et al., 2013). However, direct substrates of CHK-2 have not been identified, and the molecular mechanisms by which CHK-2 controls chromosome dynamics are therefore unknown. Based on cytological observations, the existence of a mechanism linking meiotic chromosome dynamics with cell-cycle progression has been inferred in C. elegans. Polarized nuclear organization is greatly extended in mutants that disrupt synapsis (Colaiácovo et al., 2003, MacQueen et al., 2002), hinting that cell-cycle progression is delayed. Molecular markers of early prophase, including SUN-1 phosphorylation and chromosomal localization of DSB-1/2, also persist longer in mutants that are proficient for synapsis but fail to establish crossovers (Rosu et al., 2013, Stamper et al., 2013, Woglar et al., 2013), implying that meiotic recombination is also subject to surveillance. However, it has been unclear whether these responses occur through the same feedback circuit because the molecular basis for this regulation has not been elucidated.