An ATM D-compartmentalization in DNA damage response

Abstract

How chromatin configuration impacts DNA repair is an emerging question. A recent study by Arnould et al. shows that ATM orchestrates a new chromatin compartment (D compartment) following DNA double-strand breaks and establishes that this compartment enhances cellular response to such breaks but also introduces a risk to genome integrity.

Keywords: ATM; D compartment; DNA damage response; DNA repair; chromatin compartmentalization; genome integrity.

Figure 1.. Schematic of D compartment formation following DNA double-strand break (DSB) in the nucleus.

Chromatin is structured into topologically associating domains (TADs) or contact domains that are further subdivided into distinct A and B compartments, along with various subcompartments (such as A1, A2 and B1-B4), associated with active and repressed chromatin, respectively (A). Upon the induction of DSBs, the damaged TADs become spatially isolated from the surrounding environment and give rise to a specialized compartment referred to as the “D compartment” (B). The formation of the D compartment is orchestrated by factors such as ATM activity, the accumulation of R-loops, and polymer-polymer phase separation. Notably, the D compartment comprises not just DSBs but also genes upregulated in response to DNA damage and this spatial arrangement contributes to the activation of those DNA damage response (DDR)-upregulated genes (C). However, there is a trade-off involved, as the close proximity of DSBs and DDR genes within the D compartment can potentially lead to translocation events that pose a risk to genome integrity.