Figure 10. Pathways implicated in the formation of foldback inversion GCRs.

DNA damage, which is not limited to DSBs, can initiate hairpin formation. Hairpin extension by DNA synthesis could occur by several mechanisms: strand-displacement synthesis, a migrating D-loop, or simple gap-filling synthesis. These mechanisms generate two major types of intermediates: a centromere-containing chromosome fragment with a partially extended and dynamically available 3' ssDNA end or, after DNA replication, a dicentric chromosome V which undergoes breakage during mitosis. The 3' ssDNA end or the broken dicentric chromosome can then participate in multiple types of secondary rearrangements ultimately yielding a monocentric GCR with telomeres at both ends. These rearrangements can be formed in a single step if the resulting GCR is monocentric; however, many of the complex GCRs observed are consistent with multiple rounds of rearrangement and likely involve additional dicentric intermediates (not shown). Most resolution products can be generated from either class of intermediate; however, the ura3-52/URA3 product, GCRs with multiple foldback inversions, and GCRs that duplicate all of chrV and delete of one of the two centromeres are suggestive of only one of the two proposed intermediates, as indicated.