Drosophila stem loop binding protein coordinates accumulation of mature histone mRNA with cell cycle progression

Replication-associated histone genes encode the only metazoan mRNAs that la ck polyA tails, ending instead in a conserved 26-nt sequence that forms a s tem-loop. Most of the regulation of mammalian histone mRNA is posttranscrip tional and mediated by this unique 3' end. Stem-loop-binding protein (SLBP) binds to the histone mRNA 3' end and is thought to participate in all aspe cts of histone mRNA metabolism, including cell cycle regulation. To examine SLBP function genetically, we have cloned the gene encoding Drosophila SLB P (dSLBP) by a yeast three-hybrid method and have isolated mutations in dSL B. dSLBP function is required both zygotically and maternally. Strong dSLBP alleles cause zygotic lethality late in development and result in producti on of stable histone mRNA that accumulates in nonreplicating cells. These h istone mRNAs are cytoplasmic and have polyadenylated 3' ends like other pol ymerase II transcripts. Hypomorphic dSLBP alleles support zygotic developme nt but cause female sterility. Eggs from these females contain dramatically reduced levels of histone mRNA, and mutant embryos are not able to complet e the syncytial embryonic cycles. This is in part because of a failure of c hromosome condensation at mitosis that blocks normal anaphase. These data d emonstrate that dSLBP is required in vivo for 3' end processing of histone pre-mRNA, and that this is an essential function for development. Moreover, dSLBP-dependent processing plays an important role in coupling histone mRN A production with the cell cycle.