Apr 3, 2020

Hyperactive end joining repair mediates resistance to DNA damaging therapy in p53-deficient cells

BioRxiv : the Preprint Server for Biology
R. J. KumarGaorav P Gupta


TP53 mutations in cancer are associated with poor patient outcomes and resistance to DNA damaging therapies. However, the mechanisms underlying treatment resistance in p53-deficient cells remain poorly characterized. Here, we show that p53-deficient cells exhibit hyperactive repair of therapy-induced DNA double strand breaks (DSBs), which is suppressed by inhibition of DNA-dependent protein kinase (DNA-PK). Single-cell analyses of DSB repair kinetics and cell cycle state transitions reveal an essential role for DNA-PK in suppressing S phase DNA damage and mitotic catastrophe in p53-deficient cells. Yet, a subset of p53-deficient cells exhibit intrinsic resistance to therapeutic DSBs due to a repair pathway that is not sensitive to DNA-PK inhibition. We show that p53 deficiency induces overexpression of DNA Polymerase Theta (Pol Q), which mediates an alternative end-joining repair pathway that becomes hyperactivated by DNA-PK inhibition. Combined inhibition of DNA-PK and Pol Q restores therapeutic DNA damage sensitivity in p53-deficient cells. Thus, our study identifies two targetable DSB end joining pathways that can be suppressed as a strategy to overcome resistance to DNA-damaging therapies in p53-deficient cancers.

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Mentioned in this Paper

Ambystoma californiense
Real-Time Polymerase Chain Reaction
Laboratory Procedures
N1 protein, Ambystoma mexicanum

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