Using the zebrafish animal model and human RPE1 cells, we demonstrate that SPRTN protease and Tyrosyl DNA phosphodiesterase 1 (TDP1) repair endogenous, camptothecin and formaldehyde-induced DPCs. Main conclusions from the paper are:

(1)       Beyond its recognized role in the repair of Topoisomerase 1 (TOP1)-DPCs, Tdp1 is important for the resolution of H3-DPCs in vivo and in cell models, and potentially for other 3' end-trapped DPCs.

(2)       SPRTN protease is responsible for the repair of a broad spectrum of DPCs, TOP1- and H3-DPCs, both in vivo and in cell models.

(3)       TDP1 and SPRTN act in different DPCR pathways for the resolution of endogenous DPCs, including TOP1- DPCs. However, they act epistatically to resolve endogenous H3-DPCs, both in vivo and in cell models.

(4)       Following DPC induction by camptothecin and formaldehyde, TDP1 and SPRTN act epistatically in the repair of total, TOP1-, and H3-DPCs, both in vivo and in cell models.

(5)       When comparing two systems used to study DPCR: human RPE1 cells and zebrafish embryos, we observed similar patterns of DPC dynamics, both after gene disruption and after exposure to camptothecin and formaldehyde.

(6)       The novel role of TDP1 in the repair of cellular DPCs and histone-DPCs should be considered for its implications for the development of cancer therapies. Combination therapy targeting SPRTN and TDP1 could be a promising strategy to treat cancers along with irinotecan and topotecan which are already used in clinics to treat ovarian, colorectal, and recurrent small cell lung cancer.