Molecular Characterization of the HRP1/DSE Complex

$130,397S06FY2006GMNIH

University Of Puerto Rico Rio Piedras, San Juan PR

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Abstract

Messenger (mRNA) degradation is a process that plays an important role in the regulation of gene expression, mRNA decay rates vary greatly and can be modulated in response to environmental signals. Many studies have demonstrated that mRNA turnover can be linked to translation. One pathway that has been extensively studied and clearly exemplifies the link between translation and mRNA turnover is the nonsense-mediated mRNA decay pathway. In both prokaryotes and eukaryotes, nonsense mutations in a gene can accelerate the decay of the mRNA transcribed from that gene. Previous results have demonstrated that, in addition to a nonsense-codon, downstream sequence elements (DSE) located 3' from the stop codon are required to promote nonsense-mediated mRNA decay. Further, mutations in UPF1, UPF2, and UPF3 result in an increased accumulation of nonsense-containing mRNAS while having no effect on the abundance of most wild-type transcripts. More recently, we have identified HRP1, as a trans-acting factor involved in this pathway. Based on these studies, we have outlined the identification and characterization of several cis-acting elements and trans-acting factors involved in modulating the activity of the NMD pathway. Our main research goal is to further characterize the NMD pathway. Based on our results, we will characterize the downstream sequence elements required for promoting nonsense-mediated mRNA decay. We will continue to characterize at both the molecular and biochemical levels the role of the HRP1/DSE complex in the nonsense-mediated mRNA decay pathway. We will also focus on the identification and characterization of trans-acting factors involved in nonsense-mediated mRNA decay pathway that are related to HRPI. The yeast Saccharomyces cerevisiae will be used as our model system to understand this process. With the aid of molecular, genetic and biochemical approaches, we intend to gain more understanding on how these factors are involved in nucleocytoplasmic transport, mRNA turnover and translation.

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