PGBD5 promotes site-specific oncogenic mutations in human tumors
de Stanchina, E
Nature Publishing Group
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Henssen, A., Koche, R., Zhuang, J., Jiang, E., Reed, C., Eisenberg, A., Still, E., et al. (2017). PGBD5 promotes site-specific oncogenic mutations in human tumors. Nature Genetics, 49 (7), 1005-1014. https://doi.org/10.1038/ng.3866
Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.
embryonal neoplasms, mutagenesis
This work was supported by funding from NIH K08 CA160660, P30 CA008748, U54 OD020355, UL1 TR000457, P50 CA140146, Spanish Ministerio de Economía y Competitividad SAF2014-60293-R, Cancer Research UK, the Wellcome Trust, the Starr Cancer Consortium, the Burroughs Wellcome Fund, the Sarcoma Foundation of America, the Matthew Larson Foundation, the Josie Robertson Investigator Program, and the Rita Allen Foundation. A.G.H. is supported by the Berliner Krebsgesellschaft e.V. and the Berlin Institute of Health. A.K. is supported as a Damon Runyon– Richard Lumsden Foundation Clinical Investigator.
Cancer Research UK (A18796)
External DOI: https://doi.org/10.1038/ng.3866
This record's URL: https://www.repository.cam.ac.uk/handle/1810/266736