PT  - JOURNAL ARTICLE
AU  - Diego Dibitetto
AU  - Jennie R. Sims
AU  - Carolline F.R. Ascenção
AU  - Kevin Feng
AU  - Raimundo Freire
AU  - Marcus B. Smolka
TI  - ATR Inhibitors as Potent Modulators of DNA End Resection Capacity
AID  - 10.1101/2020.01.13.905059
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.13.905059
4099  - http://biorxiv.org/content/early/2020/01/14/2020.01.13.905059.short
4100  - http://biorxiv.org/content/early/2020/01/14/2020.01.13.905059.full
AB  - DNA end resection is a key step in homologous recombination-mediated DNA repair. The ability to manipulate resection capacity is expected to be a powerful strategy to rationally modulate DNA repair outcomes in cancer cells and induce selective cell lethality. However, clinically compatible strategies to manipulate resection are not yet well established. Here we find that long-term inhibition of the ATR kinase has a drastic effect on DNA end resection. Inhibition of ATR over multiple cell division cycles depletes the pool of pro-resection factors and prevents RAD51 as well as RAD52-mediated DNA repair, leading to toxic end-joining and hypersensitivity to PARP inhibitors. The effect is markedly distinct from acute ATR inhibition, which blocks RAD51-mediated repair but not resection and RAD52-mediated repair. Our findings reveal a key pro-resection function for ATR and define how ATR inhibitors can be used for effective manipulation of DNA end resection capacity and DNA repair outcomes in cancer cells.