As mammalian cells go through the cell cycle they replicate their chromosomes during S-phase. Successful replication requires not only replication of DNA but also the synthesis of large amounts of histone proteins to package the newly replicated DNA into chromatin. The histone mRNAs are a unique class of mRNAs and are the only mRNAs that lack a polyA tail. They end instead in a conserved stemloop which is the major cis- element responsible for coordinate regulation of histone mRNAs are the posttranscriptional level. Biosynthesis of histone mRNAs requires a single processing reaction, cleavage of the pre-mRNA to form the mature mRNA. This reaction is regulated during the cell cycle, as is the stability of histone mRNA. We propose to identify the factor(s) directly involved in cleavage of histone pre-mRNA, by purifying the processing complex and to also identify which of these factors that are involved in regulating this process. Histone mRNAs are rapidly degraded when DNA replication is inhibited. We will determine the pathway of histone mRNA degradation and the factors involved in initiating and regulating the degradation of histone mRNAs. Finally we will elucidate the signal transduction pathways that transmit the information that DNA replication has ceased in the nucleus to degradation of the histone mRNA in the cytoplasm. Laymans description: Histone proteins are the proteins complexed with DNA in the chromosomes. Proper chromosome replication requires synthesis of both DNA and histones, and these two processes are tightly coupled. We will determine the factors critical for both histone mRNA synthesis and degradation, and novel factors provide potential new chemotherapy targets, as well as helping us to understand the control of cell growth.
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