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Synthesis-dependent strand annealing

Synthesis-dependent strand annealing (SDSA) is a major mechanism of homology-directed repair of DNA double-strand breaks (DSBs). Although many of the features of SDSA were first suggested in 1976, the double-Holliday junction model proposed in 1983 was favored by many researchers. In 1994, studies of double-strand gap repair in Drosophila were found to be incompatible with the double-Holliday junction model, leading researchers to propose a model they called synthesis-dependent strand annealing. Subsequent studies of meiotic recombination in S. cerevisiae found that non-crossover products appear earlier than double-Holliday junctions or crossover products, challenging the previous notion that both crossover and non-crossover products are produced by double-Holliday junctions and leading the authors to propose that non-crossover products are generated through SDSA.

Enzymes employed in SDSA during meiosis
Assembly of a nucleoprotein filament comprising single-stranded DNA (ssDNA) and the RecA homolog, Rad51, is a key step necessary for homology search during recombination. In the budding yeast Saccharomyces cerevisiae, Srs2 translocase dismantles Rad51 filaments during meiosis. By directly interacting with Rad51, Srs2 dislodges Rad51 from nucleoprotein filaments thereby inhibiting Rad51-dependent formation of joint molecules and D-loop structures. This dismantling activity is specific for Rad51 since Srs2 does not dismantle DMC1 (a meiosis-specific Rad51 homolog), Rad52 (a Rad 51 mediator) or replication protein A (RPA, a single-stranded DNA binding protein). Srs2 promotes the non-crossover SDSA pathway, apparently by regulating RAD51 binding during strand exchange. Divergence between SDSA and double-Holliday junction occurs when the D-loop is disassembled allow the nascent strand to anneal to other resected end of the DSB (in the double-Holliday junction model the strand displaced by D-loop extension anneals to the other end of the DSB in "2nd end capture"). Research in Drosophila melanogaster identified the Bloom syndrome helicase (Blm) as the enzyme promoting disassembly of the D-loop. Similarly, S. cerevisiae Sgs1, an ortholog of BLM, appears to be a central regulator of most of the recombination events that occur during S. cerevisiae meiosis. Sgs1(BLM) may disassemble D-loop structures analogous to early strand invasion intermediates and thus promote NCO formation by SDSA. As reviewed by Uringa et al. the RTEL1 helicase is proposed to regulate recombination during meiosis in the worm Caenorhabditis elegans. RTEL1 is a key protein in repair of DSBs. It disrupts D-loops and is thought to promote NCO outcomes through SDSA. The number of DSBs created during meiosis can substantially exceed the number of final CO events. In the plant Arabidopsis thaliana, only about 4% of DSBs are repaired by CO recombination, suggesting that most DSBs are repaired by NCO recombination. Data based on tetrad analysis from several species of fungi show that only a minority (on average about 34%) of recombination events during meiosis are COs (see Whitehouse, Tables 19 and 38 for summaries of data from S. cerevisiae, Podospora anserina, Sordaria fimicola and Sordaria brevicollis). In the fruit fly D. melanogaster during meiosis in females there is at least a 3:1 ratio of NCOs to COs. These observations indicate that the majority of recombination events during meiosis are NCOs, and suggest that SDSA is the principal pathway for recombination during meiosis. == References ==
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