Several DNA double-strand break (DSB) repair pathways have been characterized. However how the proper mechanism is selected at each DSB is far to be understood. In a publication out in Nucleic Acids Research, a team at IPBS provides mechanistic insights on how specific DNA double-strand breaks induced by a family of anticancer agents are directed towards the proper DNA repair pathway. In addition, they provide a rationale for the use of specific inhibitors to affect this choice, forcing the inadequate mechanism to be used leading to toxic DNA repair events, a strategy that could be used to improve the efficiency of some current anticancer treatments.
Most non surgery-based anticancer treatments use drugs or physical agents that damage cancer cells DNA, ultimately resulting into cancer cells death. The most harmful DNA damage induced by anticancer treatments is the DNA double-strand break (DSB), that can bear a single DNA end or can be two ended depending on the DNA-breaking agent. Two-ended DSBs are efficiently fixed by gluing back the two DNA ends together by a DNA repair mechanism called Non Homologous End-Joining (NHEJ). In contrast, the repair of single-ended DNA double-strand breaks is more complex and relies on another DNA repair mechanism called Homologous Recombination (HR) that copies the missing information from the sister chromatid. These two repair pathways limit the toxicity of DSBs and therefore determine the efficacy of anticancer treatments. However since they potentially compete at DNA ends, they also need to be coordinated.
The Calsou’s team at IPBS previously discovered that a critical step in the correct repair of single-ended DSBs by the HR process is the removal of the NHEJ key protein KU from DNA ends (Chanut, Britton et al. Nat commun. 2016). Here, we establish that ATM, the main protein kinase activated by single-ended DSBs, has a critical role in orientating the DNA repair choice towards HR through phosphorylating several substrates, including the CtIP-MRN nuclease complex and the NHEJ protein DNA-PKcs, both phosphorylations being critical to release the NHEJ proteins from DNA ends. Importantly, we show that ATM inhibition results in failure to remove NHEJ proteins, in improper ligation of distant DNA ends producing chromosomal aberrations and ultimately cell death due to single-ended DNA DSB being driven inadequately towards toxic DNA repair by NHEJ. Several drugs have already been developed to inhibit ATM. These discoveries pave the way to the setting of new combination therapies using the ATM inhibitors to increase the efficacy of some current anticancer treatments.
Figure: Proper repair of single-ended DSBs (left panel) requires the phosphorylations by the ATM kinase of both the nuclease complex CtIP-MRN and of the NHEJ protein DNA-PKcs. These phosphorylations are critical to evict the NHEJ proteins Ku-DNA-PKcs from DNA ends. When ATM is inhibited (right panel), NHEJ proteins stably accumulate on seDSBs and generate toxic DNA repair products by joining distant DNA ends leading to cell death. © Sébastien Britton
Britton S, Chanut P, Delteil C, Barboule N, Frit P, Calsou P. ATM antagonizes NHEJ proteins assembly and DNA-ends synapsis at single-ended DNA double strand breaks. Nucleic Acids Res. 2020 Sep 5:gkaa723. doi: 10.1093/nar/gkaa723. Online ahead of print. PMID: 32890395
Sébastien Britton | CNRS Researcher | Sebastien.Britton@ipbs.fr | Twitter: @SebBritton1 | +33 5 61 17 59 07