Synthesis-dependent strand annealing (SDSA)

In genetics, the initial processes involved in repair of a double-strand break by synthesis-dependent strand annealing (SDSA) are identical to those in the double Holliday junction model, and have been most extensively studied in yeast species Saccharomyces cerevisiae. Following a double-stranded break, a protein complex (MRX) binds to either end of the break, working with DNA nucleases to carry out resection, resulting in 5' end digest to produce 3' overhangs of single-stranded DNA (see Figure). These overhangs are then bound to form a nucleoprotein filament, which can then locate DNA sequences similar to one of the 3' overhangs, initiating a single-stranded strand invasion into the DNA duplex containing these sequences. Once strand invasion has occurred, a displacement loop, or D-loop, is formed, at which point either SDSA or a double Holliday junction occurs.

Homologous recombination via the SDSA pathway occurs in both mitotic and meiotic cells as an important mechanism of non-crossover recombination, and was first suggested as a model in 1976, acquiring its current name in 1994. As the double Holliday junction model was the first posited in order to explain this phenomenon, various versions of the SDSA model were later proposed to explain heteroduplex DNA configurations that did not match predictions of the double Holliday junction model. Studies in S. cerevisiae found that non-crossover products appear earlier than double Holliday junctions or crossover products, which challenged the previous notion that both crossover and non-crossover products are produced by double Holliday junctions.

In the SDSA model, repair of double-stranded breaks occurs without the formation of a double Holliday junction, such that the two processes of homologous recombination are identical until just after D-loop formation. In yeast, the D-loop is formed by strand invasion with the help of proteins Rad51 and Rad52, and is then acted on by DNA helicase Srs2 to prevent formation of the double Holliday junction in order for the SDSA pathway to occur. The invading 3' strand is thus extended along the recipient homologous DNA duplex by DNA polymerase in the 5' to 3' direction, such that the D-loop physically translocates – a process referred to as bubble migration DNA synthesis. The resulting single Holliday junction then slides down the DNA duplex in the same direction in a process called branch migration, displacing the extended strand from the template strand. This displaced strand pops up to form a 3' overhang in the original double-stranded break duplex, which can then anneal to the opposite end of the original break through complementary base pairing. Thus DNA synthesis fills in gaps left over from annealing, and extends both ends of the still present single stranded DNA break, ligating all remaining gaps to produce recombinant non-crossover DNA.

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