Repair-associated epigenetic memory: A conceptual framework for persistent chromatin signatures following DNA double-Strand break repair.

DNA double-strand breaks (DSBs) represent one of the most deleterious forms of genomic damage and are repaired primarily through non-homologous end joining (NHEJ) and homologous recombination (HR). Although these pathways efficiently restore DNA sequence integrity, increasing evidence indicates that DNA repair is accompanied by extensive chromatin remodeling involving histone modifications, nucleosome repositioning, DNA methylation changes, and recruitment of chromatin-associated regulatory proteins. Whether these epigenetic alterations are completely reversed following repair remains unresolved. Recent studies have reported persistent chromatin-associated features after DNA repair, including prolonged γH2AX retention, altered histone modification profiles, localized DNA methylation changes, and sustained differences in chromatin accessibility. However, their biological significance remains controversial, as they may reflect stable epigenetic alterations, delayed chromatin restoration, persistent DNA damage signaling, or adaptive cellular responses. In this review, we critically examine current evidence linking DNA damage responses with long-term chromatin remodeling and evaluate whether existing data support the concept of repair-associated epigenetic memory. We integrate findings from chromatin dynamics, epigenetic regulation, genome maintenance, radiation biology, aging, and cancer, while discussing methodological limitations and alternative interpretations. Particular attention is given to emerging approaches, including CRISPR-mediated DSB systems, single-cell epigenomics, and high-resolution chromatin profiling, that may distinguish transient repair-associated chromatin changes from persistent epigenetic alterations. Rather than presenting repair-associated epigenetic memory as an established mechanism, we propose it as a testable conceptual framework that may broaden current understanding of genome maintenance beyond DNA sequence fidelity and guide future studies of aging, genome stability, radiation responses, and disease susceptibility.