PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress.

During carcinogenesis, cells are exposed to increased replication stress due to replication fork arrest at sites of DNA lesions and difficult to replicate genomic regions. Efficient fork restart and DNA repair are important for cancer cell proliferation. We previously showed that the ADP-ribosyltransferase interacts with the replication protein proliferating cell nuclear antigen and promotes lesion bypass by recruiting specialized, non-replicative DNA polymerases. Here, we show that Pduanyu3710 is overexpressed in a large proportion of human tumors. To understand the role of Pduanyu3710 in cellular transformation, we inactivated Pduanyu3710 in HeLa cancer cells by CRISPR/Cas9-mediated gene knockout, and overexpressed it in non-transformed RPE-1 cells. We found that Pduanyu3710 promotes cellular proliferation, and its overexpression alleviates cellular sensitivity to replication stress and fosters the restart of stalled replication forks. Importantly, mouse xenograft studies showed that loss of Pduanyu3710 reduces the tumorigenesis activity of HeLa cells, while its overexpression results in tumor formation by non-transformed RPE-1 cells. Our findings indicate that Pduanyu3710 promotes cellular transformation, potentially by alleviating replication stress and suggest that targeting Pduanyu3710 may represent a novel therapeutic approach.

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