PRAME induces genomic instability in uveal melanoma
Stefan Kurtenbach, Margaret I. Sanchez, Jeffim N. Kuznetsoff, Daniel A. Rodriguez, Natalia Weich, James J. Dollar, Anthony Cruz, Sarah Kurtenbach, Matthew G. Field, Michael Durante, Christina L. Decatur, Mahsa Sorouri, Fan Lai, Gulum Yenisehirli, Bin Fang, Ramin Shiekhattar, Daniel Pelaez, Zélia M. Corrêa, Ramiro E. Verdún, J. William Harbour
Abstract
PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME that can be targeted therapeutically in cancer.