Repair of DNA double-strand breaks leaves heritable impairment to genome function

Abstract

SummaryHaving suffered a DNA breakage, a genomic locus undergoes alterations in 3-D chromatin architecture to facilitate signaling and repair. While cells possess mechanisms to repair damaged DNA, it is unknown whether similar options exist to restore the neighboring chromatin to its naïve state. Here, we show that a single DNA double-strand break (DSB) within the topologically associated domain (TAD) harboring the c-MYC locus leaves behind lasting chromatin alterations, which persist after completion of DNA repair and feature conformational changes, increased chromatin compaction and reduced retention of both coding and non-coding RNA species. Unexpectedly, all these newly acquired features of post-repair chromatin are transmitted to subsequent cell generations, where they manifest as heritable functional impairments of the c-MYC locus. These findings uncover a hitherto concealed dimension of DNA breakage, which we term post-repair chromatin fatigue, and which confers heritable impairment of gene function beyond the repair of primary DNA lesions.