Checkpoint adaptation in repair-deficient cells drives aneuploidy and resistance to genotoxic agents

Abstract

Human cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ repair-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge. We demonstrate that adaptation inhibition, either pharmacologically, or genetically, drastically reduces the occurrence of resistant cells. Additionally, the aneuploid phenotypes of the resistant cells can be specifically targeted to induce cytotoxicity. We provide evidence that TORC1 inhibition with rapamycin, in combination with DNA damaging agents, can prevent both checkpoint adaptation and the continued growth of aneuploid resistant cells.

Adaptation in replicative senescence: a risky business

“…It was initially shown that adaptation is important for survival of irradiated diploid cells when HR is compromised, while at the same time promoting genomic instability in the surviving progeny (Galgoczy and Toczyski 2001). This is supported by a recent study showing that adaptation to genotoxic challenge of HR-deficient diploid cells leads to aneuploid progeny that develops some form of resistance to a second genotoxic challenge (Bender et al 2018). To follow on a similar idea, in another setting, adaptation is required to survive telomere uncapping by loss of Cdc13 in established telomerase-independent survivors (Mersaoui et al 2015).…”

DNA Damage Stress: Cui Prodest?

“…This surveillance mechanism provides time to repair the damage, and only when repair has been successful, the checkpoint is extinguished and cells re-enter into the cell cycle [1,10,12,46,77,82,83]. In unicellular organisms, if DNA repair is not possible, cells can overcome DNA Damage through checkpoint adaptation [15,21,71,77,84]. Interestingly, mounting evidence indicates that this concept is not only found in unicellular eukaryotes like yeast but it might be extended also in multicellular organisms [10,16,76,77,85].…”

“…For instance most cells that undergo checkpoint adaptation die, whereas some cells survive; surviving cells face two different fates: Some cells will die in subsequent phases of the cell cycle, but a small number of cells will survive and divide with damaged DNA [References [85,86,87] and references there in]. In line with this model, it has been demonstrated that in repair-defective diploid yeast, nearly all cells undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge [84]. An important consequence of this finding was the demonstration that adaptation inhibition, either pharmacologically or genetically, drastically reduces the occurrence of resistant cells [87,88,89].…”

“…Cancer is often regarded as an asexual evolution in which cancer cells arise through the sequential acquisition of beneficial mutations that should confer an increased fitness to the adapted cells [94,95,96]. Checkpoint adaptation serves as a mechanism by which cells become adapted to stressful conditions [16,77,84,85,89,92]. As described above, in this process the interaction between DNA repair pathways and cell cycle checkpoints determines cell fate decision and prevents neoplastic transformation.…”