Messenger RNA production by RNA polymerase II (pol II) is central to the life of
cells. The amount of messenger transcribed from each gene determines the amount of each corresponding
protein that is made. For this reason, the process of mRNA synthesis, or transcription, is extremely
carefully regulated by the cell. Corrupted regulation of mRNA synthesis is a major cause of cancer.
Indeed, many of the oncogenes responsible for causing cancer, code for sequence specific transcription
factors whose function is to control mRNA production. Our lab has found that certain transcription
factors can stimulate the elongation of RNA transcripts by pol II. One aspect of our research is
aimed at understanding the molecular basis for how elongation is controlled by transcription factors.
To make functional, a mRNA requires synthesis of a primary transcript and
processing of the transcript into its mature form. The processing is carried out by a complex set of
proteins which add a cap at the 5' end, splice out introns and add a polyA tail at the 3' end.
Transcripts made by RNA polymerases other than pol II are not processed correctly into mature mRNA in
vivo. A mechanism clearly exists to couple transcription by pol II with the specific RNA processing
events responsible for maturation of mRNA and we are trying to work out its molecular details. Our
lab uses genetic and biochemical approaches to ask how the transcriptional machinery interacts with
the processing machinery to achieve co-ordinated synthesis and maturation of transcripts made by pol
II. We have identified a protein domain at the C-terminus of the pol II large subunit called the
CTD which is involved in targeting RNA processing factors to pol II transcripts. Our working
hypothesis is that synthesis and processing of mRNA precursors is carried out in the nucleus by a
'mRNA factory' complex which comprises pol II and processing factors held together by contacts with
the CTD.
Specific projects:
- How does the pol II CTD influence elongation of transcripts in response to sequence specific activators anad repressors?
- What genes are involved in control of transcriptional elongation by pol II in budding yeast?
- How does the cleavage/polyadenylation factor, CstF bind to the CTD and is this interaction necessary for mRNA 3’ processing in vivo?
- What is the role of the pol II CTD in processing of mRNAs in budding yeast?
- How does the CTD influence the RNA splicing reaction?
- Do sequence specific factors which regulate transcription also influence RNA processing?
Selected Publications
McCracken S., Fong, N., Yankulov K., Ballantyne S., Pan,
G., Greenblatt J., Patterson S., Wickens M., and Bentley
D. (1997) The C-Terminal Domain of RNA Polymerase II
Couples mRNA Processing to Transcription" Nature 385:
357-361.
McCracken S., Fong N.,
Rosonina E., Yankulov K., Brothers S., Siderovski, D.,
Hessel, A., Foster, S., Amgen EST Program, Shuman S.,
and Bentley D. (1997) 5' Capping Enzymes are Targeted to
pre-mRNA by Binding to the Phosphorylated C-Terminal
Domain of RNA Polymerase II. Genes and Dev., 11:
3306-3318.
Yankulov K. and
Bentley D. (1998) Tat cofactors and transcriptional
elongation. Curr. Biol. 8: 447-450.
McNeil, B., Agah, H.
and Bentley D. (1998)Activated Transcription Independent
of the RNA Polymerase II Holoenzyme in Budding Yeast
Genes and Dev., 12: 2510-2521.
Bentley, D.(1998)
RNA processing: A tale of two tails, Nature (News and
Views) 395:21-22.
McCracken, S. Rosonina, E., Fong, N., Sikes, M. Beyer,
A., O'Hare, K., Shuman, S., and Bentley, D. (1999) Role
of RNA Polymerase II Carboxy-terminal Domain in
Coordinating Transcription with RNA ProcessingCold
Spring Harbor Symposium on Quantitative Biol. LXLLL,
301-309.
Schroeder, S. Schwer, B. Shuman, S. and Bentley D.
(2000) Dynamic Association of Capping Enzymes with
Transcribing RNA polymerase II, Genes and Dev.
14:2435-2440.
Fong, N. and Bentley D.
(2001) Capping, Splicing and 3' Processing are
Independently Stimulated by RNA Polymerase II: Different
Functions for Different Segments of the CTD, Genes and
Dev. 15:1783-17.
Bentley, D (2002)
The mRNA Assembly Line: Transcription and Processing
Machines in the same Factory.Curr. Opin. Cell. Biol.
14:336-342.
Licatalosi, D. Geiger, G. Minet, M. Schroeder, S., Cilli
K. McNeil, J. and Bentley, D.(2002) Functional
Interaction of Yeast Pre-mRNA 3'-End Processing Factors
with RNA Polymerase II Mol. Cell. 9:1101-1111.
Fong N, Bird G, Vigneron M, Bentley DL. (2003)A 10 residue motif at the
C-terminus of the RNA pol II CTD is required for transcription, splicing and 3' end processing
EMBO J. 22:4274-82.
de la Mata M, Alonso C, Kadener S, Fededa, J. Blaustein M, Pelisch F, Cramer P, Bentley D,
and Kornblihtt A. A (2003) Slow Schroeder, S., Zorio, D., Schwer, B., Shuman, S., and Bentley, D. (2004). A
Function of Yeast mRNA Cap Methyltransferase, Abd1, in transcription by RNA Polymerase II. Mol. Cell 13, 377-387.
Zorio, D and Bentley D. (2004) The link between mRNA processing and transcription: communication
works both ways, Exp. Cell. Res. 296:91-97.
Bird, G. Zorio, D. and Bentley, D. (2004) RNA Polymerase II CTD phosphorylation is required for
co-transcriptional pre-mRNA splicing and 3' end formation, Mol. Cell. Biol. 24: 8963-9.
Luo, W. and Bentley (2004) A Ribonucleolytic Rat Torpedoes RNA Polymerase II, Cell,
119:911-914.
Bentley, D.(2005) Rules of engagement:co-transcriptional recruitment of pre-mRNA prcessing
factors Curr. Opin. Cell. Biol. 17:251-256.
Bird, G. Fong, N., Gatlin J. Farabaugh, S., and Bentley (2005) Ribozyme cleavage reveals connections
between mRNA release from the site of transcription and pre-mRNA processing Mol. Cell. 20:747-758.
Luo, W. Johnson, A. and . Bentley, D (2006) The role of Rat1 in coupling mRNA 3¹ end processing to transcription termination: implications for a unified allosteric-torpedo model. Genes Dev. 20:954-965.
Seward, D. Cubberley, G. Kim, S. Schonewald, M. Zhang, L. Tripet, B. and Bentley, D (2007) Demethylation of trimethylated histone H3 Lys4 in vivo by
JARID1 JmjC proteins. Nature Structural and Mol. Biol.14:240-242.
Glover-Cutter, K., Kim, S, Espinosa, J. and Bentley, D. (2008) RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nature Structural and Mol. Biol. 15:71-75
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