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

Upon DNA breakage, a genomic locus undergoes alterations in three-dimensional chromatin architecture to facilitate signaling and repair. Although cells possess mechanisms to repair damaged DNA, it is unknown whether the surrounding chromatin is restored to its naïve state. We show that a single DNA double-strand break (DSB) within a topologically associated domain (TAD) harboring conformation-sensitive genes causes lasting chromatin alterations, which persist after completion of DNA repair and feature topological rearrangements and loss of local RNA species. These newly acquired features of postrepair chromatin are transmitted to daughter cells and manifest as heritable impairments of gene expression. These findings uncover a hitherto concealed dimension of DNA breakage, which we term postrepair chromatin fatigue and which confers heritable impairment of gene function beyond DNA repair.