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TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
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TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
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Journal Article
TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
2017
Overview
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.
DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ DNA
/ DNA topoisomerase (ATP-hydrolysing)
/ DNA Topoisomerases, Type II - genetics
/ DNA Topoisomerases, Type II - metabolism
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Leukemia
/ Nuclear Proteins - metabolism
/ Poly-ADP-Ribose Binding Proteins - genetics
/ Poly-ADP-Ribose Binding Proteins - metabolism
/ Science
/ Transcription Factors - genetics
