Academic journal article Genetics

Pseudosynapsis and Decreased Stringency of Meiotic Repair Pathway Choice on the Hemizygous Sex Chromosome of Caenorhabditis Elegans Males

Academic journal article Genetics

Pseudosynapsis and Decreased Stringency of Meiotic Repair Pathway Choice on the Hemizygous Sex Chromosome of Caenorhabditis Elegans Males

Article excerpt

MEIOSIS is essential for the formation of haploid game- tes for sexual reproduction. Accurate chromosome segregation during meiosis relies on homology between ma- ternal and paternal homologous chromosomes to drive pairing, synapsis, and crossover (CO) recombination. The presence of differentiated sex chromosomes in the heterogametic sex re- quires modification of these homology-dependent processes. This is significant as the largely nonhomologous X and Y chromosomes in human males display a higher rate of non- disjunction than autosomes, resulting in infertility and de- velopmental disorders such as Klinefelter and Turner syndromes (Shi et al. 2001; Lange et al. 2009). It is cur- rently unknown how meiosis is altered to accommodate hemizygous sex chromosomes.

Of critical importance to meiotic chromosome segregation is the formation of double-strand breaks (DSBs) catalyzed by the conserved topoisomerase Spo11 and repair by homolo- gous recombination (HR) to generate crossovers (Keeney et al. 1997; Dernburg et al. 1998). Spo11-induced DSBs are processed by CtIP/Com1/Sae2, the MRN (Mrell-Rad50- Nbs1) complex and multiple nucleases to facilitate repair by HR (Terasawa et al. 2008; Manfrini et al. 2010; Zakharyevich et al. 2010; Garcia et al. 2011). Recent studies in Caenorhab- ditis elegans have revealed that COM-1 and MRE-11 promote HR by inhibiting direct religation of DSBs by nonhomologous end joining (NHEJ) (Lemmens et al. 2013; Yin and Smolikove 2013). The importance of inhibiting error-prone pathways during meiosis is also exemplified by studies in Drosophila, where multiple barriers to NHEJ have been uncovered by mutational analyses (Joyce et al. 2012). In mouse oocytes, an error-prone single-strand annealing (SSA) pathway can process extra-chromosomal DNA. SSA requires only small stretches of homology within a single DNA duplex and results in deletions (Fiorenza et al. 2001); however, the prevalence of this pathway in meiosis has not been investigated.

In addition to a bias toward repair through HR, the choice of repair template is also tightly regulated during meiosis. Unlike somatic cells where the sister chromatid is the preferred template, meiotic DSBs are preferentially repaired using the homolog. This homolog bias is imposed through regulation of the meiotic recombination machinery as well as meiosis-specific chromosomal axis components and cohesins (Couteau et al. 2004; Niu et al. 2005; Niu et al. 2009; Kim et al. 2010; Ho and Burgess 2011; Hong et al. 2013; Shin et al. 2013; Yan and McKee 2013). Thus, meiotic prophase events have evolved to drive homologous chromo- some interactions to ensure formation of crossovers for proper segregation at the meiosis I division. Nonetheless, studies in Saccharomyces cerevisiae and C. elegans have revealed that the use of the sister chromatid as a template for DSB repair in meiosis occurs and is important for main- taining genome stability (Bickel et al. 2010; Goldfarb and Lichten 2010).

Sex chromosomes of the heterogametic sex are largely nonhomologous and therefore require adaptation of these homology-dependent meiotic processes. Interestingly, even the homologous pseudoautosomal region(s) (PARs) of mammalian sex chromosomes require modification of both chromosome structure and the meiotic recombination ma- chinery to promote crossovers (Kauppi et al. 2011). Regard- less of the extent of homology, meiotic DSBs are induced along the length of sex chromosomes in male C. elegans, mice, and humans (Ashley et al. 1995; Moens et al. 1997; Sciurano et al. 2006; Jaramillo-Lambert and Engebrecht 2010; Checchi and Engebrecht 2011). The hemizygous regions of sex chromosomes subsequently undergo meiotic sex chromosome inactivation (MSCI), which is characterized by elaboration of a specialized heterochromatin domain and transcriptional silencing (Turner 2007). One proposed func- tion of MSCI is to prevent recombination between nonho- mologous regions of sex chromosomes (McKee and Handel 1993). …

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