The Mnd1 Protein Forms a Complex with Hop2 To Promote Homologous Chromosome Pairing and Meiotic Double-Strand Break Repair

Abstract

The hop2 mutant of Saccharomyces cerevisiae arrests in meiosis with extensive synaptonemal complex (SC) formation between nonhomologous chromosomes. A screen for multicopy suppressors of a hop2-ts allele identified the MND1 gene. The mnd1-null mutant arrests in meiotic prophase, with most double-strand breaks (DSBs) unrepaired. A low level of mature recombinants is produced, and the Rad51 protein accumulates at numerous foci along chromosomes. SC formation is incomplete, and homolog pairing is severely reduced. The Mnd1 protein localizes to chromatin throughout meiotic prophase, and this localization requires Hop2. Unlike recombination enzymes such as Rad51, Mnd1 localizes to chromosomes even in mutants that fail to initiate meiotic recombination. The Hop2 and Mnd1 proteins coimmunoprecipitate from meiotic cell extracts. These results suggest that Hop2 and Mnd1 work as a complex to promote meiotic chromosome pairing and DSB repair. The identification of Hop2 and Mnd1 homologs in other organisms suggests that the function of this complex is conserved among eukaryotes.Meiosis is a special type of cell division cycle that produces haploid gametes from diploid parental cells. At the first nuclear division of meiosis, sister chromatids remain associated, while homologous chromosomes segregate to opposite poles of the spindle apparatus. This reductional chromosome segregation is preceded by a lengthy prophase during which homologous chromosomes pair with each other, undergo high levels of genetic recombination, and engage in synaptonemal complex (SC) formation. These interactions between homologs are necessary prerequisites to the correct segregation of chromosomes at meiosis I.Meiotic recombination in Saccharomyces cerevisiae and other organisms initiates with double-strand breaks (DSBs), which are catalyzed by a topoisomerase-like protein known as Spo11 (21). DSBs are processed to expose single-stranded tails with 3Ј termini (6, 44), which invade homologous sequences in nonsister chromatids (5,31,40). Strand invasion results in the formation of joint molecules, whose resolution gives rise to crossover and noncrossover products (2, 18, 39). In budding yeast, several proteins are required for efficient strand invasion, but the RecA homolog Rad51 is thought to provide the principal strand-exchange activity (45; reviewed in reference 30). Rad51 and accessory proteins accumulate at discrete foci on meiotic chromosomes, during the period of DSB repair (4,14).Meiotic cell cycle progression is tightly coupled to the status of meiotic recombination events. If DSBs are formed but their subsequent repair is prevented by mutation, then a cell cycle checkpoint (the pachytene checkpoint) causes cells to arrest in mid-meiotic prophase (reviewed in reference 3). This arrest can be alleviated by a second mutation that prevents DSB formation; for example, a spo11 mutation restores sporulation in dmc1 and hop2 strains that normally arrest with hyperresected but unrepaired DSBs (6, 23). Thus, recombination intermediates appear to act a...

Positive Role of the Mammalian TBPIP/HOP2 Protein in DMC1-mediated Homologous Pairing

“…These results suggest that, during meiotic recombination, TB-PIP/HOP2 binds to the donor dsDNA, which does not contain DSBs, and DMC1 is assembled on the recipient ssDNA tails at DSB sites independently. Actually the yeast Hop2 protein binds to chromatin before the loading of the Rad51 and Dmc1 proteins, and this Hop2 localization is observed even in the absence of DSBs (22,37). These facts are consistent with a model in which TBPIP/HOP2 first binds to dsDNA in the DMC1-mediated homologous pairing during meiosis (28).…”

“…The MND1 gene is also required for meiotic recombination (38). The mnd1-null mutant exhibits a strikingly similar phenotype to that of the hop2-null mutant (37,38). This genetic evidence suggests that the HOP2 and MND1 proteins function as a complex to promote meiotic chromosome pairing, and the HOP2-MND1 complex may be a cofactor for the RAD51 and DMC1 recombinases.…”

“…The yeast Hop2 protein reportedly forms a complex with the Mnd1 protein, which has been identified as a multicopy suppressor of a temperature-sensitive hop2 mutant allele (37). The MND1 gene is also required for meiotic recombination (38).…”

Irregular telomeres impair meiotic synapsis and recombination in mice

“…Telomere-associated meiotic protein (Ndj1) is required for tethering meiotic telomeres to the nuclear periphery (7,38). Also, proteins Hop2 and Mnd1 work as a complex to promote meiotic chromosome pairing (39). Mammalian MutS homologue 5 and other proteins, such as FK506-binding protein (Fkbp6), also are required for chromosome pairing in meiosis (40,41).…”

SSP2 and OSW1, Two Sporulation-Specific Genes Involved in Spore Morphogenesis in Saccharomyces cerevisiae

“…Cells were then added to Poly-l-lysine coated slides and rinsed once with PBS followed by PBS 1 0.1% NP-40. Guinea pig anti-GFP antibody (Tsubouchi and Roeder 2002) was diluted 1:100 in PBS 1 1% BSA and used to stain cells. After overnight incubation at 4°, cells were rinsed with PBS, then PBS 1 0.1% NP-40, and then PBS.…”