Break-induced replication links microsatellite expansion to complex genome rearrangements

The instability of microsatellite DNA repeats is responsible for at least 40 neurodegenerative diseases. Recently, Mirkin and co-workers presented a novel mechanism for microsatellite expansions based on break-induced replication (BIR) at sites of microsatellite-induced replication stalling and fork collapse. The BIR model aims to explain single-step, large expansions of CAG/CTG trinucleotide repeats in dividing cells. BIR has been characterized extensively in Saccharomyces cerevisiae as a mechanism to repair broken DNA replication forks (single-ended DSBs) and degraded telomeric DNA. However, the structural footprints of BIR-like DSB repair have been recognized in human genomic instability and tied to the etiology of diverse developmental diseases; thus, the implications of the paper by Kim et al. (Kim JC, Harris ST, Dinter T, Shah KA, et al., Nat Struct Mol Biol 24: 55–60) extend beyond trinucleotide repeat expansion in yeast and microsatellite instability in human neurological disorders. Significantly, insight into BIR-like repair can explain certain pathways of complex genome rearrangements (CGRs) initiated at non-B form microsatellite DNA in human cancers.

Break-induced replication (BIR) and genome instability. BIR initiates at sites of microsatellite replication fork collapse (arrowhead). Sister chromatid (black) microsatellite misalignment leads to expansion or contraction. BIR fork collapse allows cycles of error-prone microhomology-mediated BIR (MMBIR), and homology-directed or homeologous recombination to nonhomologous chromosomes (color segments). (Not to scale.)

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