PARP10 promotes cellular proliferation and tumorigenesis by alleviating replication stress.

Published on Sep 28, 2018in Nucleic Acids Research11.501
· DOI :10.1093/NAR/GKY658
Emily M. Schleicher4
Estimated H-index: 4
(PSU: Pennsylvania State University),
Adri M. Galvan2
Estimated H-index: 2
(PSU: Pennsylvania State University)
+ 2 AuthorsClaudia M. Nicolae17
Estimated H-index: 17
(PSU: Pennsylvania State University)
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 PARP10 interacts with the replication protein proliferating cell nuclear antigen and promotes lesion bypass by recruiting specialized, non-replicative DNA polymerases. Here, we show that PARP10 is overexpressed in a large proportion of human tumors. To understand the role of PARP10 in cellular transformation, we inactivated PARP10 in HeLa cancer cells by CRISPR/Cas9-mediated gene knockout, and overexpressed it in non-transformed RPE-1 cells. We found that PARP10 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 PARP10 reduces the tumorigenesis activity of HeLa cells, while its overexpression results in tumor formation by non-transformed RPE-1 cells. Our findings indicate that PARP10 promotes cellular transformation, potentially by alleviating replication stress and suggest that targeting PARP10 may represent a novel therapeutic approach.
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