Break‐induced replication plays a prominent role in long‐range repeat‐mediated deletion

다국어 초록 (Multilingual Abstract)

Repetitive DNA sequences are often associated with chromosomal rearrangements in cancers. Conventionally, single‐strand annealing (SSA) is thought to mediate homology‐directed repair of double‐strand breaks (DSBs) between two repeats, causing repeat‐mediated deletion (RMD). In this report, we demonstrate that break‐induced replication (BIR) is used predominantly over SSA in mammalian cells for mediating RMD, especially when repeats are far apart. We show that SSA becomes inefficient in mammalian cells when the distance between the DSBs and the repeats is increased to the 1–2 kb range, while BIR‐mediated RMD (BIR/RMD) can act over a long distance (e.g., ~ 100–200 kb) when the DSB is close to one repeat. Importantly, oncogene expression potentiates BIR/RMD but not SSA, and BIR/RMD is used more frequently at single‐ended DSBs formed at collapsed replication forks than at double‐ended DSBs. In contrast to short‐range SSA, H2AX is required for long‐range BIR/RMD, and sequence divergence strongly suppresses BIR/RMD in a manner partially dependent on MSH2. Our finding that BIR/RMD has a more important role than SSA in mammalian cells has a significant impact on the understanding of repeat‐mediated rearrangements associated with oncogenesis.










Repeat‐mediated DNA deletion (RMD) is frequently associated with oncogenic chromosomal rearrangements and conventionally occurs via single‐strand annealing (SSA). However, mammalian cells appear to prefer break‐induced replication (BIR) over SSA for recombination between repeat‐associated double‐strand breaks (DSBs).



BIR, not SSA, is used for recombination between identical repeats when a DSB is localized close to one repeat but far apart from the other one.

BIR can act over a long distance (e.g. ˜100–200 kb) to mediate RMD.

Oncogene overexpression stimulates BIR/RMD.

In contrast to short‐range SSA, histone variant H2AX is required for long‐range BIR/RMD.


Mammalian cells preferentially use BIR rather than single‐strand annealing for long‐distance recombination between repetitive DNA sequences associated with oncogenic chromosomal rearrangements.