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Genome stability and instability during repair of a broken chromosome

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Double-strand breaks in DNA pose a serious threat to genome integrity. Such breaks can be repaired by nonhomologous end-joining, which often results in alterations of DNA sequence, or by homologous recombination in which the DSB is repaired by using an intact, identical or nearly identical sequence as a template. However, even DSB repair by gene conversion is associated with a highly elevated risk of associated mutation. Such mutations often have a “signature” associated with slippage or template switching of the repair DNA polymerases. We show that pairs of such slippage events can occur as often as once every 100 repair events. Similar template switching is found in another DSB repair mechanism, termed break-induced replication. These types of instability my underlie some of the complex rearrangements seen in human developmental diseases or in cancer cell chromosomes exhibiting chromothripsis. The role of chromatin in DSB will also be discussed.

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