Figure 1.

Sources of DNA double‐strand breaks formed during DNA replication. Red stars indicate the positions of DNA double‐strand ends. (A) Replication fork reversal. A four‐way ‘chicken‐foot’ structure can be generated when parental DNA strands re‐pair and newly replicated strands anneal. This forms a DNA double‐strand end and a Holliday junction, which may be cleaved to generate a broken chromosome 55, 56, 57. (B) Replication fork collapse. A one‐ended DSB can be generated when a DNA replication fork encounters a nick on one of the template strands 58. (C) Replication fork rear‐ending. Two one‐ended DSBs can be formed when a DNA replication fork is arrested and the subsequent DNA replication forks replicate this arrested fork 59. (D) Secondary structure cleavage. A DNA secondary structure, such as a hairpin, may form during DNA replication. A two‐ended DSB can be generated when a structure‐specific nuclease, such as SbcCD (Rad50/Mre11), cleaves this sequence 60. (E) Replication fork restart at a 3′ flap. A one‐ended DSB may be formed if a 3′ flap is generated during the termination of DNA replication and acts as a template for initiation of DNA synthesis and the assembly of a new replication fork 21. (F) Template‐switching with replication fork reversal. Template‐switching may occur when two replication forks collide. The two newly replicated strands would then act as reciprocal templates, which would result in DNA over‐replication. To eliminate this over‐replication, one of the replication forks might reverse, forming a DNA double‐strand end that can be degraded 23. (G) Reverse‐restart of an arrested replication fork. Following replication fork arrest, incorrect loading of the replicative helicase to a newly replicated DNA strand would result in the establishment of a new fork proceeding in the reverse direction. This reaction would generate a DNA double‐strand end 17.