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Recombination-restarted replication makes inverted chromosome fusions at inverted repeats


Impediments to DNA replication are known to induce gross chromosomal rearrangements (GCRs) and copy-number variations (CNVs). GCRs and CNVs underlie human genomic disorders1 and are a feature of cancer2. During cancer development, environmental factors and oncogene-driven proliferation promote replication stress. Resulting GCRs and CNVs are proposed to contribute to cancer development and therapy resistance3. When stress arrests replication, the replisome remains associated with the fork DNA (stalled fork) and is protected by the inter-S-phase checkpoint. Stalled forks efficiently resume when the stress is relieved. However, if the polymerases dissociate from the fork (fork collapse) or the fork structure breaks (broken fork), replication restart can proceed either by homologous recombination or microhomology-primed re-initiation4,5. Here we ascertain the consequences of replication with a fork restarted by homologous recombination in fission yeast. We identify a new mechanism of chromosomal rearrangement through the observation that recombination-restarted forks have a considerably high propensity to execute a U-turn at small inverted repeats (up to 1 in 40 replication events). We propose that the error-prone nature of restarted forks contributes to the generation of GCRs and gene amplification in cancer, and to non-recurrent CNVs in genomic disorders.

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Figure 1: Alternative mechanism for inverted chromosomal fusion.
Figure 2: Rearrangement frequency is dependent on the repeat size and interrupting-sequence size.
Figure 3: Fidelity of HR-restarted fork improves with distance.
Figure 4: U-turn at palindrome centre is chief mechanism for inverted fusion in double- RTS1 constructs.


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We thank E. Hoffman, J. Baxter, M. Neale and members of the Carr and Murray laboratories for discussions. J.M.M. acknowledges Cancer Research UK (CRUK) grant C9601/A9484: A.M.C. acknowledges Medical Research Council (MRC) grant G0600233.

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I.M., K.M. and S.A.S. performed experiments. J.M.M., K.M. and A.M.C. wrote the manuscript. All authors contributed to experimental design.

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Correspondence to Antony M. Carr.

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The authors declare no competing financial interests.

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Mizuno, K., Miyabe, I., Schalbetter, S. et al. Recombination-restarted replication makes inverted chromosome fusions at inverted repeats. Nature 493, 246–249 (2013).

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