Tying synaptonemal complex initiation to the formation and programmed repair of DNA double-strand breaks

Abstract

During meiosis, homologous chromosomes recombine and become closely apposed along their lengths within the synaptonemal complex (SC). In part because Spo11 is required both to make the double-strand breaks (DSBs) that initiate recombination and to promote normal SC formation in many organisms, it is clear that these two processes are intimately coupled. The molecular nature of this linkage is not well understood, but it has been proposed that SC formation initiates locally at the sites of ongoing recombination and in particular at the subset of sites that will eventually give rise to crossovers. To test this hypothesis, we examined further the relationship between DSBs and SC formation in Saccharomyces cerevisiae. SCs were monitored in a series of spo11 missense mutants with varying DSB frequencies. Alleles that blocked DSB formation gave SC phenotypes indistinguishable from a deletion mutant, and partial loss-of-function mutations with progressively more severe DSB defects caused corresponding defects in SC formation. These results strongly correlate SC formation with Spo11 catalytic activity per se. Numbers of Zip3 complexes on chromosomes, thought to represent the sites of SC initiation, also declined when Spo11 activity decreased, but in a markedly nonlinear fashion: hypomorphic spo11 alleles caused larger defects in DSB formation than in Zip3 complex formation. This nonlinear response of Zip3 closely paralleled the response of crossover recombination products. The quantitative relationship between Zip3 foci, SC formation, and crossing over strongly implicates crossover-designated recombination intermediates as the sites of SC initiation.T wo prominent features of meiotic prophase are homologous recombination and formation of the synaptonemal complex (SC). Recombination establishes physical connections between homologous chromosomes in the form of crossovers, which help orient chromosomes properly on the meiosis I spindle. The widely conserved SC connects homologous chromosomes along their lengths during a portion of meiotic prophase and consists of two lateral elements, each formed along the axis connecting a pair of sister chromatids, and a central element linking the lateral elements together (reviewed in refs. 1 and 2).Chromosome synapsis is tightly coupled to homologous recombination in many organisms. The DNA double-strand breaks (DSBs) that initiate recombination occur before synapsis begins in budding yeast (3), and cytological features (e.g., histone H2AX phosphorylation and formation of strand exchange protein complexes) indicate that the same is true in other fungi, higher plants, and mammals (4-8). DSBs are created by the Spo11 protein (9, 10), and spo11 null mutants in many organisms are defective for SC formation (11-16). In some cases, exogenous DSBs can at least partially substitute for Spo11 in SC formation (15)(16)(17). Moreover, mutations that block processing of DSBs once they are formed (e.g., rad50S, dmc1) also cause defects in SC formation (18)(19)(20). These results place Spo11 action...

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

“…SCs are zipper-like structures, which are assembled between homologous chromosomes during the prophase of the meiosis I. Formation of SCs is essential for proper parental chromosome segregation before meiotic division (78). We immunostained the surface cell spreads with antibodies against SYCP3 (a marker of the chromosome core) and SYCP1 (that marks completely synapsed chromosomes) and analyzed the pattern of chromosome synapsing.…”

Meiotic recombination and male infertility: from basic science to clinical reality?

“…18 Additionally, yeast SPO11 mutants show a range of phenotypes from partial loss of function, to complete loss of DSB formation. 59 Both spermatocytes and oocytes from SPO11 2/2 mice have been demonstrated to undergo apoptosis during pachytene and diplotene, respectively. 18 Although mutations in SPO11 and its regulatory sequences do not appear to be a common contributor to human male infertility, when they are present, formation of DSBs appears to be greatly affected.…”

Local chromosome context is a major determinant of crossover pathway biochemistry during budding yeast meiosis

“…Meiotic DSB repair occurs concurrently with homolog pairing and synapsis (Bö rner et al, 2004;Padmore et al, 1991), and efficient homolog synapsis requires wild-type DSB levels (Henderson and Keeney, 2004), indicating that multiple interhomolog interactions along a chromosome are needed for stable homolog pairing. To account for the reduced levels and MutLg-independence of VDE-initiated COs in spo11 mutants, we suggest that a single VDE-DSB is not sufficient to promote stable homolog pairing, and that additional DSBs along a chromosome are needed to promote stable homolog pairing, which in turn is needed to form ZMM protein-containing structures that stabilize JMs and recruit MutLg.…”