Loss of the histone pre-mRNA processing factor stem-loop binding protein in Drosophila causes genomic instability and impaired cellular proliferation.
BACKGROUND
Metazoan 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.


RESULTS
In 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
These 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.
Salzler
Harmony R
HR
Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
Davidson
Jean M
JM
Montgomery
Nathan D
ND
Duronio
Robert J
RJ
D000818:Animals; D049109:Cell Proliferation; D055012:Chromosomal Position Effects / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics*; D022041:Euchromatin / Q000378:metabolism; D005819:Genetic Markers; D042822:Genomic Instability / Q000235:genetics*; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D019656:Loss of Heterozygosity / Q000235:genetics; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D011123:Polyploidy; D012322:RNA Precursors / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D016196:S Phase
D029721:Drosophila Proteins; D022041:Euchromatin; D005819:Genetic Markers; D006570:Heterochromatin; D006657:Histones; D012322:RNA Precursors; D016601:RNA-Binding Proteins; C490155:SLBP protein, Drosophila