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Abstract
The inability to repair damaged DNA severely compromises the integrity of any organism. In eukaryotes, the DNA damage response (DDR) operates within chromatin, a tightly organized DNA–histone complex in a non-random manner within the nucleus. Chromatin thus orchestrates various cellular processes, including repair. Here, we examine the chromatin landscape before, during, and after the DNA damage, focusing on double strand breaks (DSBs). We study how chromatin is modified during the repair process, not only around the damaged region (in cis), but also genome-wide (in trans). Recent evidence has highlighted a complex landscape in which different chromatin parameters (stiffness, compaction, loops) are transiently modified, defining “codes” for each specific stage of the DDR. We illustrate a novel aspect of DDR where chromatin modifications contribute to the movement of DSB-damaged chromatin, as well as undamaged chromatin, ensuring the mobilization of DSBs, their clustering, and their repair processes.
Highlights
The impact of genome organization on DNA transactions began to be appreciated when it became clear that genomes were not totally randomly organized, but followed organizing principles [1–4]
It was observed by single particle tracking (SPT) and photo-activated localization microscopy (PALM) that some repair proteins, such as Rad52, present liquid droplet capacity since it exhibits a high level of intrinsic disorder [92,93] (Figure 2c)
Deciphering the relationship between chromosome organization and genome activity is essential for understanding genomic processes such as gene expression, maintenance of genome stability, or deregulation in diseases (Figure 3)
Summary
The impact of genome organization on DNA transactions began to be appreciated when it became clear that genomes were not totally randomly organized, but followed organizing principles [1–4]. The spatial arrangement of eukaryotic genomes is based on two distinct scales of organization. The mechanistic links between structure and function are still in their infancy, especially when DNA damages occur Such damages can be due to chemical, physical, or biological factors including ultraviolet light or X-radiation, the incorporation of incorrect bases during DNA replication, or the presence of free radicals because of metabolic pathways. While the fine coordination of DSB detection, signaling, and repair is better understood, the impact of chromatin architecture and chromosome spatial organization is just beginning. We begin by outlining how organization of chromosomes is based on (i) the SMC complexes that have a preponderant role both at the chromatin level and more globally on the folding of chromosomes and (ii) anchoring at the nuclear periphery
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