Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability.
Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability.
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DOI：
10.1038/ncomms10549
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发表时间：
2016-02-04
影响因子：
16.6
通讯作者：
Honjo T
中科院分区：
文献类型：
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作者：
Husain A;Begum NA;Taniguchi T;Taniguchi H;Kobayashi M;Honjo T
拓扑异构酶1是一种缓解超螺旋张力的酶，与神经退行性疾病相关的转录相关诱变和基因组不稳定性以及激活诱导的胞苷脱氨酶有关。从TOP1相关蛋白的蛋白质组学分析，我们确定SMARCA 4，ATP依赖性染色质重塑; FACT，组蛋白伴侣;和H3 K4 me 3，转录活性染色质标记。在这里，我们表明，SMARCA 4在B细胞系中的敲除减少了TOP1向染色质的募集，并导致Igh/c-Myc染色体易位、可变区和开关区突变以及负超螺旋性的增加，所有这些都是在TOP1敲除后观察到的。相反，FACT敲低抑制TOP1与H3 K4 me 3的结合，并严重减少DNA切割和Igh/c-Myc易位，对TOP1向染色质的募集没有显著影响。因此，我们提出SMARCA 4参与TOP1向一般染色质的募集，而FACT是TOP1在非B DNA含有染色质处结合H3 K4 me 3以进行位点特异性切割所需的。 拓扑异构酶1（TOP 1）在转录过程中DNA链解旋时缓解超螺旋张力。在这里，Husain等人报道SMARCA 4是一种ATP依赖性染色质重塑剂，与TOP 1相关，并抑制转录相关的基因组不稳定性。
Topoisomerase 1, an enzyme that relieves superhelical tension, is implicated in transcription-associated mutagenesis and genome instability-associated with neurodegenerative diseases as well as activation-induced cytidine deaminase. From proteomic analysis of TOP1-associated proteins, we identify SMARCA4, an ATP-dependent chromatin remodeller; FACT, a histone chaperone; and H3K4me3, a transcriptionally active chromatin marker. Here we show that SMARCA4 knockdown in a B-cell line decreases TOP1 recruitment to chromatin, and leads to increases in Igh/c-Myc chromosomal translocations, variable and switch region mutations and negative superhelicity, all of which are also observed in response to TOP1 knockdown. In contrast, FACT knockdown inhibits association of TOP1 with H3K4me3, and severely reduces DNA cleavage and Igh/c-Myc translocations, without significant effect on TOP1 recruitment to chromatin. We thus propose that SMARCA4 is involved in the TOP1 recruitment to general chromatin, whereas FACT is required for TOP1 binding to H3K4me3 at non-B DNA containing chromatin for the site-specific cleavage. Topoisomerase 1 (TOP1) relieves superhelical tension when DNA strands are unwound during transcription. Here, Husain et al. report that SMARCA4, an ATP-dependent chromatin remodeller, is associated with TOP1 and suppresses transcription-associated genomic instability.