Abstract
DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation ‘hotspot’, MLL. Moreover, we find that TDP2 suppresses chromosome rearrangements induced by TOP2 and reduces TOP2-induced chromosome translocations that arise during gene transcription. Interestingly, however, we implicate TDP2-dependent NHEJ in the formation of a rare subclass of translocations associated previously with therapy-related leukemia and characterized by junction sequences with 4-bp of perfect homology. Collectively, these data highlight the threat posed by TOP2-induced DSBs during transcription and demonstrate the importance of TDP2-dependent non-homologous end-joining in protecting both gene transcription and genome stability.
Highlights
DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation
tyrosyl-DNA phosphodiesterase 2 (TDP2) patient cells exhibited a significantly greater increase in micronuclei and nucleoplasmic bridges than did normal control lymphoblastoid cell lines (LCLs) following treatment with low doses of etoposide, suggesting that genome instability is increased in the absence of TDP2 at sites of TOP2-induced DSBs (Fig. 1a)
Patient cell populations exhibited a high frequency of metaphases with multiple aberrations, including complex events involving multiple chromosomes (Fig. 1c). These results demonstrate that TDP2 is required to maintain chromosome stability in human cells following the induction of DSBs by abortive TOP2 activity
Summary
DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. We show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation ‘hotspot’, MLL. We implicate TDP2-dependent NHEJ in the formation of a rare subclass of translocations associated previously with therapyrelated leukemia and characterized by junction sequences with 4-bp of perfect homology These data highlight the threat posed by TOP2-induced DSBs during transcription and demonstrate the importance of TDP2-dependent non-homologous end-joining in protecting both gene transcription and genome stability. These data highlight the threat posed by TOP2 in genome instability during gene transcription and demonstrate the importance of TDP2dependent NHEJ for suppressing this instability
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