Academic journal article Genetics

Suppression of Meiotic Recombination by CENP-B Homologs in Schizosaccharomyces Pombe

Academic journal article Genetics

Suppression of Meiotic Recombination by CENP-B Homologs in Schizosaccharomyces Pombe

Article excerpt

ABSTRACT Meiotic homologous recombination (HR) is not uniform across eukaryotic genomes, creating regions of HR hot- and coldspots. Previous study reveals that the Spo11 homolog Rec12 responsible for initiation of meiotic double-strand breaks in the fission yeast Schizosaccharomyces pombe is not targeted to Tf2 retrotransposons. However, whether Tf2s are HR coldspots is not known. Here, we show that the rates of HR across Tf2s are similar to a genome average but substantially increase in mutants deficient for the CENP-B homologs. Abp1, which is the most prominent of the CENP-B family members and acts as the primary determinant of HR suppression at Tf2s, is required to prevent gene conversion and maintain proper recombination exchange of homologous alleles flanking Tf2s. In addition, Abp1-mediated suppression of HR at Tf2s requires all three of its domains with distinct functions in transcriptional repression and higher-order genome organization. We demonstrate that HR suppression of Tf2s can be robustly maintained despite disruption to chromatin factors essential for transcriptional repression and nuclear organization of Tf2s. Intriguingly, we uncover a surprising cooperation between the histone methyltransferase Set1 responsible for histone H3 lysine 4 methylation and the nonhomologous end joining pathway in ensuring the suppression of HR at Tf2s. Our study identifies a molecular pathway involving functional cooperation between a transcription factor with epigenetic regulators and a DNA repair pathway to regulate meiotic recombination at interspersed repeats.

KEYWORDS meiosis; retrotransposons; homologous recombination; CENP-B; gene conversion; Set1; NHEJ; Condensin

MEIOSIS is a distinct cell division distinguished by the conversion of a diploid cell into haploid gametes during the sexual stages of eukaryotes. Reducing ploidy of a cell containing two different sets of chromosomes requires pairing and subsequent segregation of homologous chromosomes (Hunter et al. 2007). In most eukaryotes, pairing of homologous chromosomes is aided by the conserved topoisomerase Spo11, which generates double-strand breaks (DSBs) at preferential sites along the chromosome (Keeney et al. 2014). Repair of DSBs by homologous recombination (HR) between homologous chromosomes provides opportunities for interhomolog shuffling of alleles and a platform for proper segregation of homologous chromosomes (Petronczki et al. 2003; Keeney and Neale 2006).

Rates of HR vary across chromosomes creating regions of recombination hotspots and coldspots (Cromie et al. 2007; Pan and Keeney 2007; Ludin et al. 2008; Lichten and de Massy 2011). A variety of determinants govern hotspot formation, including transcriptional promoters, nucleosome-depleted regions, and histone modifications (Wu and Lichten 1994; Pan et al. 2011; Smagulova et al. 2011; Martin-Castellanos et al. 2013; Choi and Henderson 2015). Mapping of Spo11 binding reveals that DSB hotspots associate with trimethylation of histone H3 lysine 4 (H3K4me3) in the budding yeast Saccharomyces cerevisiae (Borde et al. 2009), mice, and humans (Buard et al. 2009; Grey et al. 2011; Smagulova et al. 2011; Baudat et al. 2013). Moreover, deletion of the H3K4me histone methyltransferase set1 in S. cerevisiae reduces meiotic DSB sites and alters the pattern of hotspots across the genome (Borde et al. 2009). While not as well-understood as hotspot formation, coldspot regions tend to associate with transcriptional repression and closed chromatin structures such as centromeres and telomeres (Petes 2001).

Structural organization of chromosomes also governs meiotic recombination. In both budding yeast and mice, DSB regions appear to organize into alternating domains of low and high DSB activities (Kauppi et al. 2011; Pan et al. 2011), suggesting a role for higher-order chromatin structures in imposing these patterns. Prior to DSB formation, chromatin becomes organized into a condensed, dynamic structure consisting of chromatin loops bound to an axis enriched for structural proteins such as cohesins, condensins, and meiosis-specific axialelement proteins (Zickler and Kleckner 1999; Borde and de Massy 2013; Keeney et al. …

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