Peter A. Beal
Students and postdocs working in the Beal laboratory use synthetic chemistry to study and control ribonucleic acids (RNAs). Our work is advancing understanding of essential basic science principles of RNA structure and recognition and is providing a platform for the development of new therapeutics targeting RNA or RNA-binding proteins. We create new RNA molecules by chemical synthesis with nucleoside analogs, introducing novel and desirable features. In addition, we synthesize new compounds capable of perturbing natural RNA function or the function of RNA-modifying enzymes. We are currently applying these approaches to the study of RNA-editing adenosine deaminases and RNA interference by short interfering RNAs (siRNAs).
Editing reactions insert, delete or modify nucleotides in RNA. ADARs (adenosine deaminases acting on RNA) are editing enzymes that convert adenosine (A) to inosine (I) in duplex RNA, a modification that has wide-ranging consequences on RNA function including altering miRNA recognition sites, redirecting RNA splicing and changing the meaning of specific codons in mRNA. Recent work has demonstrated a causal link between altered RNA editing and human disease. However, our understanding of the ADAR reaction mechanism, origin of editing site selectivity and the effect of disease-causing mutations is limited. Our lab has an on-going NIH-funded project to fill these knowledge gaps and to develop molecules capable of modulating RNA editing activity in living cells. We use a variety of techniques in this project including nucleoside analog synthesis, mechanistic enzymology, directed evolution and structural biology (in collaboration with Professor Andrew Fisher).
RNAi with modified siRNAs
Specific gene silencing via the RNA interference (RNAi) pathway offers tremendous promise for therapeutics since the technology can be broadly applied to many different gene targets. Indeed, there are several RNAi drugs currently undergoing clinical trials for a variety of diseases ranging from viral infections to cancer. However, development of RNA-based therapeutics is currently hindered by a variety of challenges, notably the difficulty of targeted delivery of the drug within the body, activation of the innate immune system and sequence selectivity for target genes. In our lab, we are improving siRNA properties through the design and synthesis of siRNAs bearing novel nucleoside analogs. These molecules have shown improved RNAi activity and selectivity with reduced immune stimulation. This project is funded by a grant from the NIH.
Education, Awards and Professional Highlights
- Fellow, Japan Society for the Promotion of Science, Kyoto University (2016)
- Program Director, NIH T32 Training Grant in Chemical Biology (2015)
- Fellow, American Association for the Advancement of Science (2012)
- Appointed to UC Davis faculty (2006)
- Robert Parry Teaching Award (2005)
- Camille Dreyfus Teacher Scholar (2000)
- NIH Postdoctoral Associate, Harvard University (1994-1996)
- Ph.D. Caltech (1994)
- Phi Beta Kappa (1989)
- B.S. University of North Dakota (1989)
- “Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity” Melissa M. Matthews†, Justin M. Thomas†, Yuxuan Zheng, Kiet Tran, Kelly J. Phelps, Anna I. Scott, Jocelyn Havel, Andrew J. Fisher and Peter A. Beal Nat. Struct. Mol. Biol. 2016 (in press).†Contributed equally.
- “Fluorescent Adenosine Analog as a Substrate for an A-to-I RNA Editing Enzyme” Rena A. Mizrahi, Dongwon Shin, Renatus W. Sinkeldam, Kelly J. Phelps, Andrea Fin, Dean J. Tantillo, Yitzhak Tor and Peter A. Beal, Angew. Chem. Int. Ed. 2015, 54, 30, 8713-8716.
- “Recognition of Duplex RNA by the Deaminase Domain of the RNA editing Enzyme ADAR2” Kelly Phelps, Kiet Tran, Tristan Eifler, Anna Erickson, Andrew J. Fisher and Peter A. Beal Nucleic Acids Res. 2015, 43, 2, 1123-1132.
- “On-enzyme refolding permits small RNA and tRNA surveillance by the CCA-adding enzyme” Claus-D. Kuhn, Jeremy E. Wilusz, Yuxuan Zheng, Peter A. Beal and Leemor Joshua-Tor Cell 2015, 160, 4, 644-658.
- “Click Modification of RNA at Adenosine: Structure and Reactivity of 7-Ethynyl- and 7-Triazolyl-8-aza-7-deazaadenosine in RNA” Kelly Phelps, José M. Ibarra-Soza, Kiet Tran, Andrew J. Fisher and Peter A. Beal ACS Chem. Biol. 2014, 9, 8, 1780-1787.
- “Short Interfering RNA Guide Strand Modifiers from Computational Screening” Kazumitsu Onizuka, Jason G. Harrison, Alexi A. Ball-Jones, José M. Ibarra-Soza, Yuxuan Zheng, Diana Ly, Walter Lam, Stephanie Mac, Dean J. Tantillo and Peter A. Beal J. Am. Chem. Soc. 2013, 135, 45, 17069-17077.
- “RNA-Seq Analysis Identifies A Novel Set of Editing Substrates for Human ADAR2 Present in Saccharomyces cerevisiae” Tristan Eifler, Subhash Pokharel and Peter A. Beal Biochemistry, 2013, 52, 45, 7857-7869.
- “Potent and Selective Inhibition of A to I RNA Editing with 2’-O-Methyl/Locked Nucleic Acid-containing Antisense Oligoribonucleotides” Rena A. Mizrahi, Nicole T. Schirle and Peter A. Beal ACS Chem. Biol. 2013, 8, 4, 832-839.
- “Nucleoside analog studies indicate mechanistic differences between RNA-editing adenosine deaminases” Rena A. Mizrahi, Kelly Phelps, Andrea Ching and Peter A. Beal Nucleic Acids Res. 2012, 40, 19, 9825-9835
- “Novel Modifications in RNA” Kelly Phelps, Alexi Morris and Peter A. Beal ACS Chem. Biol. 2012, 7, 100-109.
- “ADAR proteins: Structure and Catalytic Mechanism” Rena A. Goodman, Mark R. Macbeth and Peter A. Beal Curr. Top. Microbiol. Immunol. 2012, 353, 1-33.
- “Chemical Modification of siRNA Bases to Probe and Enhance RNA Interference” Hayden Peacock, Arunkumar Kannan, Peter A. Beal and Cynthia J. Burrows J. Org. Chem. 2011, 76, 18, 7295-7300.
- “Nucleobase and ribose modifications control immunostimulation of a microRNA 122-mimetic siRNA” Hayden Peacock, Raymond V. Fucini, Prasanna Jayalath, José M. Ibarra-Soza, Henry J. Haringsma, W. Michael Flanagan, Aarron Willingham and Peter A. Beal J. Am. Chem. Soc. 2011, 133, 24, 9200-9203.
- “RNA editing changes the lesion specificity for the DNA repair enzyme NEIL1” Jongchan Yeo, Rena A. Goodman, Nicole T. Schirle, Sheila S. David and Peter A. Beal Proc. Natl. Acad. Sci. USA 2010, 107, 48, 20715-20719.