ATM-dependent formation of a novel chromatin compartment regulates the Response to DNA Double Strand Breaks and the biogenesis of translocations

Abstract

DNA Double-Strand Breaks (DSBs) repair is essential to safeguard genome integrity but the contribution of chromosome folding into this process remains elusive. Here we unveiled basic principles of chromosome dynamics upon DSBs in mammalian cells, controlled by key kinases from the DNA Damage Response. We report that ATM is responsible for the reinforcement of topologically associating domains (TAD) that experience a DSB. ATM further drives the formation of a new chromatin sub-compartment (“D” compartment) upon clustering of damaged TADs decorated with γH2AX and 53BP1. “D” compartment formation mostly occurs in G1, is independent of cohesin and is enhanced upon DNA-PK pharmacological inhibition. Importantly, a subset of DNA damage responsive genes that are upregulated following DSBs also physically localize in the D sub-compartment and this ensures their optimal activation, providing a function for DSB clustering in activating the DNA Damage Response. However, these DSB-induced changes in genome organization also come at the expense of an increased translocations rate, which we could also detect on cancer genomes. Overall, our work provides a function for DSB-induced compartmentalization in orchestrating the DNA Damage Response and highlights the critical impact of chromosome architecture in genomic instability.

DNA double-strand break end synapsis by DNA loop extrusion

“…Importantly, given MRN's hypothesized loop extrusion activity 101 and the enrichment of MRN subunit NBS1 at DSB sites 102 , MRN itself could also function as gap-bridging LEFs, effectively achieving targeting loading of LEFs while alleviating the required fold increase in loading of cohesin at DSBs. Fifth, we speculate that LEF stabilization by DSBs may be mediated by the ATM complex, which phosphorylates cohesins and accumulates cohesins in the DSBcontaining TAD 44,103 . Finally, we note that our mechanistic understanding of loop extrusion and DSB repair is advancing rapidly, such that other factors and mechanisms are likely to be found to play a role beyond the ones mentioned above.…”

Circadian PERIOD proteins regulate TC-DSB repair through anchoring to the nuclear envelope

“…7h). Of importance, this was not the case for other DDR genes which are not targeted to the D-compartment ( PPM1D , SLC9A1 ) 25 , or for other non-induced genes ( LPHN2 , UTP18 ). Altogether these data indicate that the circadian rhythm regulates the repair and signaling of TC-DSBs by controlling their PER2-dependent anchoring to the NE and, therefore, the formation of the D-compartment, further fine-tuning the response to DSBs.…”

“…Collectively our data suggest that PER proteins prevent DSB clustering and D-compartment formation by fostering the targeting of TC-DSBs to the nuclear lamina. D-compartment formation fosters the DNA damage response, but it also comes at the expense of increased translocation rate 12,25,58 . In agreement with the above data involving PER2 in counteracting D-compartment formation, increased translocation frequency was observed upon depletion of the PER complex proteins (Fig.…”

“…D-compartment formation fosters the DNA damage response, but it also comes at the expense of increased translocation rate 12,25,58 . In agreement with the above data involving PER2 in counteracting D-compartment formation, increased translocation frequency was observed upon depletion of the PER complex proteins (Fig.…”

SPPiDDRs: a new gene family in dicot plants involved in DNA-Damage Response

“…Once DNA damage is detected in eukaryotic cells, signaling cascades are initiated by two serine/threonine kinases: ATAXIA-TELANGIECTASIA MUTATED (ATM) and ATAXIA TELANGIECTASIA-MUTATED AND RAD3-RELATED (ATR) [3][4][5] . In mammals, ATM and ATR indirectly activate p53, also known as the "guardian of the genome", which is the transcription factor (TF) that mounts and orchestrates the DNA-damage response (DDR) 6,7 Strikingly, plants lack p53, but ATM directly phosphorylates and activates the plant-specific TF SUPPRESSOR OF GAMMA IRRADIATION1 (SOG1), which is the plant master regulator of DDR. It is assumed that ATR operates similarly, even though SOG1 phosphorylation by ATR has been shown only in vitro [8][9][10] .…”