Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations
Spatial Chromosome Folding and Active Transcription Drive DNA Fragility and Formation of Oncogenic MLL Translocations
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DOI：
10.1016/j.molcel.2019.05.015
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发表时间：
2019-07-25
期刊：
影响因子：
16
通讯作者：
Roukos, Vassilis
中科院分区：
文献类型：
--
作者：
Gothe, Henrike Johanna;Bouwman, Britta Annika Maria;Roukos, Vassilis
空间染色体组织如何影响基因组完整性仍然知之甚少。在这里，我们发现由拓扑异构酶2 （TOP2）活性介导的DNA双链断裂（DSBs）在具有高转录活性的染色质环锚点上富集。复发性dsb发生在染色质环基部的ccctc结合因子（CTCF）和黏结蛋白结合位点，其频率与转录输出和方向性呈正相关。这种优先定位的生理学相关性表明，基因反复易位驱动白血病是高度转录的，并在环锚点富集。这些基因在反复出现的热点上积累dsb，这些热点依赖于TOP2亚型的活性和转录伸长来产生染色体融合。我们认为转录和3D染色体折叠共同对基因组稳定性构成威胁，并且是驱动癌症的基因组重排发生的关键因素。
How spatial chromosome organization influences genome integrity is still poorly understood. Here, we show that DNA double-strand breaks (DSBs) mediated by topoisomerase 2 (TOP2) activities are enriched at chromatin loop anchors with high transcriptional activity. Recurrent DSBs occur at CCCTC-binding factor (CTCF) and cohesin-bound sites at the bases of chromatin loops, and their frequency positively correlates with transcriptional output and directionality. The physiological relevance of this preferential positioning is indicated by the finding that genes recurrently translocating to drive leukemias are highly transcribed and are enriched at loop anchors. These genes accumulate DSBs at recurrent hotspots that give rise to chromosomal fusions relying on the activity of both TOP2 isoforms and on transcriptional elongation. We propose that transcription and 3D chromosome folding jointly pose a threat to genomic stability and are key contributors to the occurrence of genome rearrangements that drive cancer.