Abstract
A number of studies across different model systems revealed that chromatin undergoes significant changes in dynamics in response to DNA damage. These include local motion changes at damage sites, increased nuclear exploration of both damaged and undamaged loci, and directed motions to new nuclear locations associated with certain repair pathways. These studies also revealed the need for new analytical methods to identify directed motions in a context of mixed trajectories, and the importance of investigating nuclear dynamics over different time scales to identify diffusion regimes. Here we provide an overview of the current understanding of this field, including imaging and analytical methods developed to investigate nuclear dynamics in different contexts. These dynamics are essential for genome integrity. Identifying the molecular mechanisms responsible for these movements is key to understanding how their misregulation contributes to cancer and other genome instability disorders.
Highlights
CHROMATIN EXPLORES A LARGER NUCLEAR VOLUME IN RESPONSE TO DNA DAMAGEA significant number of studies in the past decade have identified essential roles for nuclear dynamics in DNA repair, during homologous recombination (HR) repair of doublestrand breaks (DSBs) (Figures 1A–D)
This change in chromatin mobility in response to DNA damage likely reflects the exploration of the nuclear space during “homology search” (Kalocsay et al, 2009; Dion et al, 2012; Miné-Hattab and Rothstein, 2012; Neumann et al, 2012; Agmon et al, 2013; Cho et al, 2014; Saad et al, 2014; Herbert et al, 2017; MinéHattab et al, 2017), i.e., the process where a resected DSB covered by a Rad51 nucleoprotein filament scans the genome in search of a homologous donor
Several techniques have been applied to study the nuclear dynamics of DSBs in different organisms, with “gold standard” approaches relying on damage induction with endonucleases or ionizing radiation (IR), and on monitoring repair sites with lacO/tetO arrays and fluorescent-tagged HR repair components (Figures 1E–G)
Summary
A significant number of studies in the past decade have identified essential roles for nuclear dynamics in DNA repair, during homologous recombination (HR) repair of doublestrand breaks (DSBs) (Figures 1A–D). Several molecular mechanisms governing chromatin dynamics in response to DSBs have been identified, and specialized pathways appear to participate in different contexts [reviewed in Amaral et al (2017); Caridi et al (2017); Zimmer (2018); Oshidari et al (2019b)] Together, these studies revealed important roles for nuclear dynamics in DSB repair, for homology search and for isolating repeated DNA sequences at high risk for aberrant recombination, enabling “safe” repair or alternative rescue pathways
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