Chromatin Remodeling, DNA Double-Strand Break Repair, and Human Disease: How a Breakup Changes You

Chromatin architecture is a central determinant of genomic stability. Effective DNA repair requires dynamic chromatin remodeling to grant repair factors timely access to lesions and to orchestrate repair pathway choice. Disruption of chromatin-regulatory mechanisms or DNA damage response pathways undermines repair fidelity and contributes to a wide spectrum of human disorders, including developmental syndromes, premature aging, and multiple cancers. Here, we review how chromatin state and remodeling complexes shape detection, signaling, and resolution of DNA double-strand breaks, and we examine how their misregulation drives disease and presents opportunities for therapeutic intervention. Specifically, we discuss how post-translational modifications and ATP-dependent chromatin remodeling complexes contribute to DNA damage repair with a particular focus on DNA double-strand breaks, one of the most deleterious DNA lesions. We summarize how chromatin remodeling and histone post-translational modifications regulate DNA repair pathway choice, and how these processes are essential for safeguarding genomic integrity and preventing human disease. Finally, we discuss emerging concepts and major unanswered questions in the context of chromatin function and DNA double-strand break repair, with a focus on exploring the emerging literature on the role of chromatin compartments and topological associated domains for orchestrating DNA repair within chromatin and safeguarding genomic stability.