Determining the molecular mechanism and functional importance of Eri1-dependent histone mRNA degradation

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Eri1-deficiency in mice results in a number of phenotypes, most prominently growth retardation, postnatal death and male sterility. The Eri1 protein is a 3 exoribonuclease and has been demonstrated to degrade RNAi-duplexes or process 5.8S rRNA molecules. Furthermore, Eri1 was found to bind to histone mRNA stem-loops for which a functional explanation remained elusive. Our current data convincingly demonstrate that Eri1 is required for replication-dependent histone mRNA degradation. Previous studies suggest that Eri1 selects histone mRNA targets by sequence-specific binding through its SAP (SAF-A/B, Acinus and PIAS) domain. Contradictory to these results, in our investigation of 5.8S rRNA processing this domain was found to be dispensable. The proposed experiments will clarify the molecular mechanism of Eri1-dependent histone mRNA degradation. We will determine mutual binding requirements in the Eri1 protein and histone mRNA and evaluate how these molecular determinants allow coordinated degradation of histone mRNAs. In addition we will search for the activity that restricts Eri1-dependent histone mRNA degradation to the end of S-phase. Studying male sterility in Eri1 knockout mice will allow us to correlate deregulation of histone mRNAs with critical alterations during sperm cell development and link the molecular mechanism to pathological changes in the animal model.