Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability

Afzal Husain, Nasim A. Begum, Takako Taniguchi, Hisaaki Taniguchi, Maki Kobayashi and Tasuku Honjo ()
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Afzal Husain: Graduate School of Medicine, Kyoto University, Yoshida-Konoe cho, Sakyo-ku
Nasim A. Begum: Graduate School of Medicine, Kyoto University, Yoshida-Konoe cho, Sakyo-ku
Takako Taniguchi: Institute for Enzyme Research, University of Tokushima
Hisaaki Taniguchi: Institute for Enzyme Research, University of Tokushima
Maki Kobayashi: Graduate School of Medicine, Kyoto University, Yoshida-Konoe cho, Sakyo-ku
Tasuku Honjo: Graduate School of Medicine, Kyoto University, Yoshida-Konoe cho, Sakyo-ku

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms10549

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