Inverted Repeat Fusion Occurs via Distinct Pathways

Inverted repeats, or reverse complementary nucleotide sequences, can base pair with one another to form hairpin or cruciform structures that can stall replication fork progression and cause DNA damage. Inappropriate DNA repair events at such stalled replication sites could lead to fusion of inverted repeats and subsequently generate chromosomal rearrangements. To gain insight into the mechanisms underlying inverted repeat fusion, Hu and colleagues created reporter cassettes in which fusion of identical or mismatched inverted repeats would allow survival on selection media. Fusion of the identical and mismatched repeat reporters (IRR and MRR) occurred spontaneously in wild-type murine embryonic stem (ES) cells and led to unstable and complex chromosome rearrangements. DNA damaging agents increased fusion of the reporters, but γ-irradiation selectively induced IRR fusion and ultraviolet light selectively induced MRR fusion, suggesting that different pathways mediate inverted repeat fusion depending on the sequence identity. Fusion of the IRR, but not the MRR, increased in ES cells lacking the Bloom syndrome mutated (BLM) RecQ helicase that regulates homologous recombination at stalled replication forks, suggesting that fusion of identical inverted repeats is dependent on BLM-regulated homologous recombination. In contrast, MRR fusion was dependent on error-free postreplication repair, which required RAD18 as well as three prime repair exonuclease 2 (TREX2), a suppressor of homologous recombination. Both IRR and MRR fusion could be induced by a low concentration of hydroxyurea, which depletes nucleotides and stalls replication forks without causing double-strand breaks, indicating that faulty replication is sufficient to activate both inverted repeat fusion pathways. These findings implicate BLM-regulated homologous recombination and RAD18/TREX2-dependent error-free postreplication repair as candidate mechanisms underlying complex chromosome rearrangements in human cancers.

Hu L, Kim TM, Son MY, Kim SA, Holland CL, Tateishi S. Two replication fork maintenance pathways fuse inverted repeats to rearrange chromosomes. Nature 2013 Sept 8 [Epub ahead of print].