Abstract
The three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. We irradiate fibroblasts, lymphoblasts, and ATM-deficient fibroblasts with 5 Gy X-rays and perform Hi-C at 30 minutes, 24 hours, or 5 days after irradiation. We observe that 3D genome changes after irradiation are cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibit an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation is not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.
Highlights
The three-dimensional structure of chromosomes plays an important role in gene expression regulation and influences the repair of radiation-induced DNA damage
To determine whether increased topologically associating domains (TADs) insulation after Ionizing radiation (IR) is linked to the DNA damage/repair pathway, we examine the 3D genome organization changes in cells with compromised double strand break repair: human fibroblasts deficient in the ataxia telangiectasia mutated (ATM) gene
We observed that X-ray irradiated BJ-5ta cells showed an elevated level of γ-H2AX protein at 30 min post-exposure followed by a decline at 24 h post-IR, indicating an efficient repair of DNA double strand break (DSB) (Fig. 1a and Supplementary Fig. 2a, b)
Summary
The three-dimensional structure of chromosomes plays an important role in gene expression regulation and influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. All tested repairproficient cell types exhibit an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation is not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair. The human genome is a linear DNA sequence, but is organized in a three-dimensional (3D) structure, which influences the proper regulation of transcription, replication, and repair[2,3,4,5]. Induced DNA damage alters the genome architecture and whether the 3D genome architecture is restored after DNA repair
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
