TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
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DOI：
10.1038/s41467-017-00307-y
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发表时间：
2017-08-10
影响因子：
16.6
通讯作者：
Caldecott, Keith W.
中科院分区：
文献类型：
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作者：
Gomez-Herreros, Fernando;Zagnoli-Vieira, Guido;Caldecott, Keith W.
拓扑异构酶II（TOP2）活性异常引起的DNA双链断裂（DSB）是基因组不稳定和染色体易位的潜在来源。TOP2诱导的DNA双链断裂部分通过酪氨酰-DNA磷酸二酯酶2（TDP 2）依赖性非同源末端连接（NHEJ）重新连接，但该过程是否抑制或促进TOP2诱导的易位尚不清楚。在这里，我们表明，TDP 2重新加入DSB在乳腺癌细胞中的转录依赖的TOP 2活性和易位的“热点”，MLL。此外，我们发现TDP 2抑制由TOP 2诱导的染色体重排，并减少基因转录过程中出现的TOP 2诱导的染色体易位。然而，有趣的是，我们暗示TDP 2依赖性NHEJ形成了一种罕见的易位亚类，这种易位以前与治疗相关的白血病相关，其特征在于具有4-bp完全同源性的连接序列。总的来说，这些数据突出了转录过程中TOP 2诱导的DSB所造成的威胁，并证明了TDP 2依赖性非同源末端连接在保护基因转录和基因组稳定性方面的重要性。
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.