Abstract
BackgroundMetazoan replication-dependent histone mRNAs terminate in a conserved stem-loop structure rather than a polyA tail. Formation of this unique mRNA 3′ end requires Stem-loop Binding Protein (SLBP), which directly binds histone pre-mRNA and stimulates 3′ end processing. The 3′ end stem-loop is necessary for all aspects of histone mRNA metabolism, including replication coupling, but its importance to organism fitness and genome maintenance in vivo have not been characterized.Methodology/Principal FindingsIn Drosophila, disruption of the Slbp gene prevents normal histone pre-mRNA processing and causes histone pre-mRNAs to utilize the canonical 3′ end processing pathway, resulting in polyadenylated histone mRNAs that are no longer properly regulated. Here we show that Slbp mutants display genomic instability, including loss of heterozygosity (LOH), increased presence of chromosome breaks, tetraploidy, and changes in position effect variegation (PEV). During imaginal disc growth, Slbp mutant cells show defects in S phase and proliferate more slowly than control cells.Conclusions/SignificanceThese data are consistent with a model in which changing the 3′ end of histone mRNA disrupts normal replication-coupled histone mRNA biosynthesis and alters chromatin assembly, resulting in genomic instability, inhibition of cell proliferation, and impaired development.
Highlights
Histones are a class of highly abundant nuclear proteins whose most basic function is to package and organize the genetic material
To gain a generalized measure of genomic instability, we developed a loss of heterozygosity (LOH) assay
We previously showed that the misprocessed, polyadenylated histone mRNAs produced in Slbp mutants are not always properly cell cycle regulated and in some tissues accumulate in cells that are not synthesizing DNA [27,29]
Summary
Histones are a class of highly abundant nuclear proteins whose most basic function is to package and organize the genetic material. In addition to organizing DNA, histones play important roles in a number of other cellular processes critical for survival and development. These include DNA repair [1], chromosome segregation [2], regulation of transcription [3], and tissue differentiation [4]. Metazoan replication-dependent histone mRNAs terminate in a conserved stem-loop structure rather than a polyA tail. Formation of this unique mRNA 39 end requires Stem-loop Binding Protein (SLBP), which directly binds histone pre-mRNA and stimulates 39 end processing. The 39 end stem-loop is necessary for all aspects of histone mRNA metabolism, including replication coupling, but its importance to organism fitness and genome maintenance in vivo have not been characterized
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