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| FACULTY BIOGRAPHY |
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| James Manley |
| JC Levi Professor |
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| Our laboratory studies several aspects of gene expression in animal cells. These include transcription of mRNA encoding genes, mRNA splicing, and mRNA polyadenylation. All three of these processes occur in the cell nucleus and require numerous protein (and in the case of splicing, RNA) factors that assemble into massive multi-subunit complexes. It is our goal to understand how the complexes assemble and function on the DNA template or pre-mRNA substrate, and to learn how these important molecules act to regulate gene expression and how they themselves are controlled. These studies involve a large number of experimental approaches, including a variety of in vitro assays, biochemical fractionation and protein purification, cDNA and genomic DNA cloning, production of recombinant proteins and antibodies, in vitro mutagenesis, and genetic analyses using a variety gene targeting approaches.
With respect to transcription, we are studying several factors that function in gene control. This includes analyzing both biochemically and genetically how certain general transcription factors, especially components of TFIID, the promoter recognition factor, function and interact with regulators and with DNA. We are also interested in the transcribing enzyme itself, RNA polymerase II, and especially with factors that allow it to elongate efficiently and eventually to terminate transcription.
Our studies on mRNA splicing address a number of different issues. We study the mechanism of pre-mRNA splicing by examining the role that small nuclear RNAs (snRNAs) play in the catalysis of splicing. We have recently shown that fragments of two of these snRNAs, U2 and U6, can by themselves catalyze reactions that resemble the authentic splicing reaction, providing the first evidence that proteins are dispensable for splicing catalysis. We are also very interested in regulation of alternative splicing, an important mechanism of gene control. We concentrate on understanding how members of the SR protein family, characterized by a human protein we co-discovered called ASF/SF2, function to modulate the selection of splice sites in alternatively spliced pre-mRNAs and to control splicing more generally; how these proteins are regulated by phosphorylation; and how they interact with other regulatory proteins.
Addition of the poly(A) tail to an mRNA is the last step in the synthesis of mRNA, and it, too, requires numerous protein factors. The polyadenylation factors, including the poly(A) polymerase itself, constitute an interesting family of proteins that interact with each other and with the mRNA precursor in novel ways. Several of these proteins play important regulatory roles in different cell types and at different stages of the cell cycle. Our recent studies have uncovered interactions with DNA repair factors and tumor suppressor proteins, which suggest an unexpected interplay between these nuclear processes
Recently we made the discovery that these three processes, transcription, splicing and polyadenylation, are all linked in an unexpected way: RNA polymerase II, long known to be responsible for synthesis of mRNA precursors, also functions directly in both splicing and polyadenylation. This requires an intriguing region of the polymerase, known as the CTD, which consists of a unique, repetitive sequence that is highly phosphorylated. We are currently studying how the CTD functions, and how its interactions contribute to gene control.
Publications Since 1995
MedLine Listing of Dr. Manley's Publications
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Representative Recent Publications
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- Kashima T, Manley JL (2003) A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy Nat Genet. [Epub ahead of print]: Article
- Chen Z, Manley JL (2003) In vivo functional analysis of the histone 3-like TAF9 and a TAF9-related factor, TAF9L J Biol Chem. [Epub ahead of print]: Article
- Shin C, Manley JL (2002) The SR protein SRp38 represses splicing in M phase cells Cell 111(3): 407-17. Article
- Valadkhan S, Manley JL. (2001) Splicing-related catalysis by protein-free snRNAs Nature 413(6857): 701-7. Article
- Calvo, O. and Manley, J.L. (2001) Evolutionarily conserved interaction between CstF-64 and PC4 links transcription, polyadenylation and termination Mol Cell 7: 1013-1023. Article
- Kleiman, F.E. and Manley, J.L. (2001) The Bard1-CstF-50 interaction links mRNA 3' end formation to DNA damage and tumor suppression Cell 104: 743-753. Article
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