Chromatin Remodeller SMARCA4 Recruits Topoisomerase 1 and Suppresses Transcription-associated Genomic Instability

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Feb 5

PMID 26842758

Citations 49

Authors

Afzal Husain

Nasim A Begum

Takako Taniguchi

Hisaaki Taniguchi

Maki Kobayashi

Tasuku Honjo

Affiliations

Soon will be listed here.

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.

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