Replication Forks Restarted by Homologous Recombination Display a High Frequency of Errors at Inverted Repeats

Abstract

Replication restart by HR at the sites of a collapsed replication fork promotes cell survival, but at the expense of increasing the potential for genome rearrangement. We have previously shown that, when a replication fork collapses within a small (~900bp) inverted repeat, homologous recombination is required to restart the collapsed fork. In the majority of cases, the restart event is effective and promotes cell survival. However, the presence of a nearby repeat (homologous sequence) results in an inappropriate template exchange in a few percent of events, producing dicentric and acentric giant palindromic chromosomes.We also studied the consequence of restarted replication fork progression through a small palindrome. We observed that restarted forks are prone to generate errors when they replicate through small inverted repeats. Thus, two distinct mechanisms can result in gross chromosomal rearrangements: 1. When replication forks collapse within a repeated sequence, incorrect homologous recombination can occur that results in repeat fusion. 2. The restarted replication fork is itself error prone, and is particularly sensitive to making errors when replicating closely spaced inverted repeats.