RT Journal Article SR Electronic T1 A genome-wide miRNA screen identifies regulators of tetraploid cell proliferation JF bioRxiv FD Cold Spring Harbor Laboratory SP 266395 DO 10.1101/266395 A1 Marc A. Vittoria A1 Elizabeth M. Shenk A1 Kevin P. O’Rourke A1 Amanda F. Bolgioni A1 Sanghee Lim A1 Victoria Kacprzak A1 Ryan J. Quinton A1 Neil J. Ganem YR 2018 UL http://biorxiv.org/content/early/2018/02/19/266395.abstract AB Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, non-transformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these anti-proliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive, gain-of-function genome-wide screen to identify miRNAs that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g. miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g. miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via downregulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.