The tumor suppressor parafibromin is required for posttranscriptional processing of histone mRNA

Parafibromin, encoded by the gene HRPT2, is a tumor suppressor protein associated with the RNA polymerase II-associated complex, Paf1 complex. HRPT2 mutations were first identified in patients with the multiple endocrine neoplasia syndrome, hyperparathyroidism-jaw tumor (HPT-JT) syndrome, and have also been found in sporadic parathyroid and renal tumors. However, the mechanisms by which parafibromin suppresses tumor formation remain unknown. In this study, we identify a novel role of parafibromin in the regulation of replication-dependent histones. Both in vitro and in vivo analyses reveal a posttranscriptional role of parafibromin in histone mRNA processing. Downregulation of parafibromin through RNA interference or in vivo mutations lead to uncleaved histone mRNA with polyadenylated tails. These results indicate that parafibromin regulates the 3′ processing of histone RNA, an essential component of the cell cycle. © 2009 Wiley-Liss, Inc.