The deubiquitination-PARylation positive feedback loop of the USP10-PARP1 axis promotes DNA damage repair and affects therapeutic efficacy of PARP1 inhibitor.

PARP1 initiates DNA repair pathways including single-strand break repair (SSBR) by recruiting multiple DNA repair factors via poly ADP-ribosylation (PARylation) of target proteins. However, how PARP1 is stabilized and activated to promote DNA damage repair remains unclear. Here we report that DNA damage generates a ROS signal, which triggers USP10 to interact with and stabilize PARP1 by deubiquitinating the K418 site in an ATM-dependent manner. In turn, PARP1 mediates PARylation of USP10 at amino acid residues D634, D645, and E648, which further promotes the deubiquitination activity of USP10 and DNA damage response to form a positive feedback loop. PARP1 is highly expressed in breast cancer tissues and positively correlates with USP10 protein levels. Moreover, breast cancer cells treated with a USP10 inhibitor show increased sensitivity to PARP1 inhibitor both in vivo and in vitro. Overall, our results unravel that the deubiquitination-PARylation positive feedback loop of the USP10-PARP1 axis promotes DNA damage repair, which might contribute to the improvement of PARP1 inhibitor efficacy in breast cancer treatment.