DNA replication: Failures and inverted fusions

DNA replication normally follows the rules passed down from Watson and Crick: the chromosome duplicates as dictated by its antiparallel strands, base-pairing and leading and lagging strand differences. Real-life replication is more complicated, fraught with perils posed by chromosome damage for one, and by transcription of genes and by other perils that disrupt progress of the DNA replication machinery. Understanding the replication fork, including DNA structures, associated replisome and its regulators, is key to understanding how cells overcome perils and minimize error. Replication fork error leads to genome rearrangements and, potentially, cell death. Interest in the replication fork and its errors has recently gained added interest by the results of deep sequencing studies of human genomes. Several pathologies are associated with sometimes-bizarre genome rearrangements suggestive of elaborate replication fork failures. To try and understand the links between the replication fork, its failure and genome rearrangements, we discuss here phases of fork behavior (stall, collapse, restart and fork failures leading to rearrangements) and analyze two examples of instability from our own studies; one in fission yeast and the other in budding yeast.