Atox1 promotes CRC progression by protecting DNA damage through interacts with a novel copper-binding protein PARP1

The copper chaperone antioxidant 1 (Atox1) is a key driver in several cancers, with increased expression associated with poor survival. Its role in colorectal cancer (CRC) had been largely unexplored. Based on TCGA data and clinical samples, we found elevated Atox1 expression in CRC. Knockdown of Atox1 suppressed cell proliferation and tumor growth in vitro and in vivo, and silencing it led to DNA damage in CRC cells. Further experiments showed that Atox1 directly interacted with Poly(ADP-ribose) polymerase 1 (PARP1) at the copper binding site and positively regulated its activity. Mechanistic studies indicated that PARP1 is a novel copper-binding protein, and excessive copper inhibited PARP1’s enzymatic activity and weakened DNA damage repair. Atox1 relieves copper’s inhibitory effect on PARP1. Targeting Atox1 with DC_AC50 also induced DNA damage, suppressed cell proliferation, and inhibited tumor growth in CRC. The combination of DC_AC50 and Olaparib had a stronger inhibitory effect on CRC growth. This research demonstrated that Atox1 interacts with PARP1, a novel copper-binding protein, by regulating DNA damage, cell proliferation, and tumor growth in CRC. The Atox1 - PARP1 axis could be a prospective therapeutic target for CRC.