Disease relevance of SPO11

• Disruption of mouse Spo11 results in infertility [1].

High impact information on SPO11

• Meiotic recombination in Saccharomyces cerevisiae is initiated by programmed DNA double-strand breaks (DSBs), a process that requires the Spo11 protein [2].
• We report that a Spo11 construct bearing the Gal4 DNA binding domain not only rescues spo11Delta spore inviability and catalyzes DSB formation at natural sites but also strongly stimulates DSB formation near Gal4 binding sites [2].
• In Saccharomyces cerevisiae, meiotic recombination is initiated by Spo11-dependent double-strand breaks (DSBs), a process that precedes homologous synapsis [3].
• Using mutations affecting the initiation of recombination (spo11) or mismatch repair (msh2 pms1 ), we demonstrate that meiotic destabilization depends on the initiation of homologous recombination at nearby DNA double-strand break (DSBs) sites and involves a 'rearranged heteroduplex' intermediate [4].
• These findings strongly implicate Spo11 as the catalytic subunit of the meiotic DNA cleavage activity [5].

Biological context of SPO11

• Deletion of the SPO11 gene decreases the length of S phase by approximately 25% [6].
• The ume3-1 allele was identified as a mutation that allowed the aberrant expression of several meiotic genes (e.g. SPO11, SPO13) during mitotic cell division in Saccharomyces cerevisiae [7].
• The specificity is achieved by selecting for mutants that produce viable spores when recombination and reductional segregation are prevented by mutations in SPO11 and SPO13 genes, but fail to yield viable spores during a normal Rec+ meiosis [8].
• The mutations of interest confer a defect in spore formation that is dependent upon a gene required for initiation of meiotic recombination and development of meiosis-specific chromosome structure (SPO11) [9].
• This conditional defect could be partially rescued by expression of untagged SPO11, but not by expression of untagged REC102, indicating that tagged REC102 is fully dominant for this synthetic phenotype [10].

Anatomical context of SPO11

• RT-PCR and in situ hybridization analyses of a time course of juvenile testis development indicate that Spo11 expression begins in early meiotic Prophase I, prior to the pachytene stage, with increasing accumulation of mRNA through the pachytene stage [11].
• Strong expression of the Spo11 message is seen in juvenile and adult testis by RNA in situ hybridization, RT-PCR, and Northern blot, with much weaker expression in thymus and brain [11].
• Mammalian SPO11 genes were found to be expressed at high levels only in testis, wherein mouse Spo11 transcript is restricted primarily to meiotic germ cells and is maximally expressed at midpachynema [12].

Associations of SPO11 with chemical compounds

• Mutagenesis, performed on SPO11, of the single tyrosine conserved between the five homologues shows that this amino acid is essential for Spo11 activity [13].
• Mutations at an invariant arginine (Arg-131) within a second conserved structural motif known as the 5Y-CAP domain, as well as three other mutations (E235A, F260R, and D290A), caused marked changes in the DSB pattern at a recombination hotspot, suggesting that Spo11p contributes directly to the choice of DNA cleavage site [14].
• These Toprim domain residues have been implicated in binding a metal ion cofactor in topoisomerases and bacterial primases, supporting the idea that DNA cleavage by Spo11p is Mg(2+) dependent [14].

Physical interactions of SPO11

• It has recently been shown that Spo11p coimmunoprecipitates with Rec102p in meiosis as well [15].
• Ski8p also functions in meiotic recombination in complex with Spo11 in yeast [16].

Enzymatic interactions of SPO11

• By analogy with the mechanism of action of known type II topoisomerases, we suggest that Spo11 catalyses the formation of double-strand breaks that initiate meiotic recombination in S. cerevisiae [13].

Regulatory relationships of SPO11

• CONCLUSION: The repairing system working in intein homing shares molecular machinery with meiotic recombination induced by Spo11p [17].
• HO endonuclease-induced recombination in yeast meiosis resembles Spo11-induced events [18].

Other interactions of SPO11

• We find that double-strand breaks occur at two specific sites associated with the hot spot and that occurrence of these breaks depends upon meiotic recombination functions RAD50 and SPO11 [19].
• We report that Mre11p transiently associates with the chromatin of Spo11-dependent DSB regions throughout the genome [20].
• Analysis of the spo11 mutant demonstrates that Red1 localization does not depend upon meiotic recombination [21].
• This study demonstrates genetic and physical interactions between the products of SPO11 and another early meiotic gene required for DSB formation, REC102 [10].
• If DSB formation is blocked (e.g., by a spo11 mutation), dephosphorylation of Mer2 and its dissociation from chromosomes are delayed [22].

Analytical, diagnostic and therapeutic context of SPO11

• Using chromatin-immunoprecipitation (ChIP), we detected the transient, noncovalent association of Spo11 with meiotic hotspots in wild-type cells [23].
• Germline transcript and mouse Spo11 expression were analyzed by RT-PCR [24].

References