Fig. 1.

Multiple DNA repair pathways are employed during double-strand break repair. After DNA DSB formation, the broken ends can be religated using minimal to no nucleotide homology through non-homologous end joining (NHEJ). Alternatively, 5′ ends are resected to expose single-stranded DNA favoring alternate routes of DSB repair. The presence of direct DNA sequence repeats may provide homologous regions that can anneal to form a contiguous chromosome in a process called single-strand annealing (SSA). Heterologous 3′ flaps are removed by the XPF endonuclease aided by Slx4 and Saw1. Alternatively, Rad51-dependent homology search and strand invasion forms a displacement loop (D-loop) to prime DNA synthesis from the 3′-OH end of the broken chromosome on an intact template. Extension of the D-loop and subsequent D-loop disruption and reannealing to the second end repairs the break via synthesis-dependent strand annealing (SDSA) resulting in noncrossover (NCO) products (Resnick 1976). Formation of an intact replication fork leads to the continuous extension of the D-loop to the end of the chromosome, defining the break-induced replication (BIR) pathway and resulting in loss of heterozygosity (LOH) (Malkova et al. 1996). The elongated D-loop forms a junction, where branch migration may lead to the formation of a single Holliday junction (sHJ). In the event of second-end capture, the displaced strand of the D-loop anneals to the other resected 3′ strand forming first two nicked Holliday junctions (nHJ) and after ligation a double Holliday junction (dHJ) (Szostak et al. 1983). Double HJs can be dissolved by the combined activities of a DNA motor protein (S. cerevisiae Sgs1 or human BLM) and a type IA topoisomerase into NCO products (Wu and Hickson 2003; Cejka et al. 2010) or resolved by coordinated endonuclease cleavage into CO or NCO products (Szostak et al. 1983). Single HJs require resolution by a nuclease and cannot be processed by a dissolution mechanism like dHJs