Affiliations

Director, Biochemistry, Biophysics & Structural Biology GPB Home Area

Associate Professor, Biological Chemistry

Member, Gene Regulation GPB Home Area, JCCC Gene Regulation Program Area

My research group is interested to understand how non-coding RNAs function by forming defined three-dimensional structures and by interacting with proteins. In particular, we are investigating how a class of small RNAs (called microRNA or miRNA) is processed in human. The projects will be investigated using X-ray crystallography, biochemistry and in vitro evolution methods. MiRNAs are involved in many important biological functions, and are emerged as a new class of oncogenes and tumor suppressors. They regulate the expression of many protein-coding genes by targeting their messenger RNAs (mRNAs) for degradation or translational repression. To become the short mature functional forms, the long primary transcripts (pri-miRNAs) need to be specifically recognized and cleaved by a series of cellular processing factors. The first step of this processing pathway involves two protein factors, Drosha (a ribonuclease III family member) and DGCR8 (an RNA binding protein). We are characterizing the RNA binding and cleavage properties of these proteins, in the hope to use the knowledge to improve the algorithms to predict new miRNA genes and to design gene knockdown technologies by mimicking pri-miRNA. We recently found surprisingly that DGCR8 is a heme-binding protein and heme is likely involved in the regulation of miRNA processing. Our findings have important implications to the biological functions of miRNAs and heme, and to the pathogenesis and therapies of diseases such as cancers and Alzheimer's disease.

Senturia, R., Laganowsky, A., Barr, I., Brooke D. Scheidemantle, B.D., and Guo, F. Dimerization and heme binding are conserved in amphibian and starfish homologues of the microRNA processing protein DGCR8. PLoS ONE. 2012; 7(7): e39688. Download Gong, M., Chen, Y., Senturia, R., Ulgherait, M., Faller, M., and Guo, F. Caspases cleave and inhibit the microRNA processing protein DiGeorge Critical Region 8. . Protein Sci. 2012; 21: 797-808. Barr, I., Smith, A.T., Chen, Y., Senturia, R., Burstyn, J.N., and Guo, F. Ferric, not ferrous, heme activates RNA-binding protein DGCR8 for primary microRNA processing. Proc. Natl. Acad. Sci. USA. 2012; 109: 1919-1924. Meer, E.J., Wang, D.O., Kim, S.M., Barr, I., Guo, F., and Martin, K.C. Identification of a cis-acting element that localizes mRNA to synapses. Proc. Natl. Acad. Sci. USA 2012; 109: 4639-4644. Barr, I., Smith, A.T., Senturia, R., Chen, Y., Scheidemantle, B.D., Burstyn, J.N., and Guo, F. DiGeorge Critical Region 8 (DGCR8) is a double-cysteine-ligated heme protein. J. Biol. Chem. 2011; 286: 16716-25. Faller, M., Toso, D., Matsunaga, M., Atanasov, I., Senturia, R., Chen, Y., Zhou, Z.H., and Guo, F. DGCR8 recognizes primary transcripts of microRNAs through highly cooperative binding and formation of higher-order structures. RNA. 2010; 16: 1570-1583. Senturia, R., Faller, M., Yin, S., Loo, J.A., Cascio, D., Sawaya, M.R., Hwang, D., Clubb, R.T., and Guo, F. Structure of the dimerization domain of DiGeorge Critical Region 8. Protein Sci. 2010; 19: 1354-1365. Miallau Linda, Faller Michael, Chiang Janet, Arbing Mark, Guo Feng, Cascio Duilio, Eisenberg David Structure and proposed activity of a member of the VapBC family of toxin-antitoxin systems. VapBC-5 from Mycobacterium tuberculosis. J, Biol. Chem. 2009; 284(1): 276-83. Wang, Q., Barr, I., Guo, F., Lee, C. Evidence of a novel RNA secondary structure in the coding region of HIV-1 pol gene. RNA. 2008; 14(12): 2478-88. Faller Michael, Guo Feng MicroRNA biogenesis: there's more than one way to skin a cat. Biochimica et biophysica acta. 2008; 1779(11): 663-7. Faller, M., Matsunaga, M., Yin, S., Loo, J., and Guo, F. Heme is involved in microRNA processing. Nature Structural & Molecular Biology 2007; 14(1): 23-29. Download Guo, F., Gooding, A.R. and Cech, T.R. Comparison of crystal structure interactions and thermodynamics for stabilizing mutations in the Tetrahymena ribozyme. RNA 2006; 12: 387-395. Download Guo, F Gooding, AR Cech, TR Structure of the Tetrahymena ribozyme: base triple sandwich and metal ion at the active site. Molecular cell. . 2004; 16(3): 351-62. Download Guo, F Cech, TR Evolution of Tetrahymena ribozyme mutants with increased structural stability. Nature structural biology. . 2002; 9(11): 855-61. Download Guo, F Cech, TR In vivo selection of better self-splicing introns in Escherichia coli: the role of the P1 extension helix of the Tetrahymena intron. RNA (New York, N.Y.) . 2002; 8(5): 647-58. Download Guo, F Gopaul, DN Van Duyne, GD Asymmetric DNA bending in the Cre-loxP site-specific recombination synapse. Proceedings of the National Academy of Sciences of the United States of America. . 1999; 96(13): 7143-8. Download Gopaul, DN Guo, F Van Duyne, GD Structure of the Holliday junction intermediate in Cre-loxP site-specific recombination. The EMBO journal. . 1998; 17(14): 4175-87. Download Guo, F., Gopaul, D.N., van Duyne, G.D. Structure of Cre recombinase complexed with DNA in a site-specific recombination synapse. Nature. 1997; 389(6646): 40-6. Download Weitz, S. H., Gong, M., Barr, I., Weiss, S., and Guo, F. Processing of microRNA primary transcripts requires heme in mammalian cells. Proc. Natl. Acad. Sci. USA. 2014; 111: 1861-1866. Quick-Cleveland, J., Jacob, J.P., Weitz, S.H., Shoffner, G., Senturia, R., and Guo, F. The DGCR8 RNA-binding heme domain recognizes primary microRNAs by clamping the hairpin. Cell Rep. 2014; 7(6): 1994-2005. Chin, R.M., Fu, X., Pai, M.Y., Vergnes, L., Hwang, H., Deng, G., Diep, S., Lomenick, B., Meli, V.S., Monsalve, G.C., Hu, E., Whelan, S.A., Wang, J.X., Jung, G., Solis, G.M., Fazlollahi, F., Kaweeteerawat, C., Quach, A., Nili, M., Krall, A.S., Godwin, H.A., Chang, H.R., Faull, K.F., Guo, F., Jiang, M., Trauger, S.A., Saghatelian, A., Braas, D., Christofk, H.R., Clarke, C.F., Teitell, M.A., Petrascheck, M., Reue, K., Jung, M.E., Frand, A.R., and Huang, J. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014; 510: 397-410. Barr, I. and Guo, F. Primary microRNA processing assay reconstituted using recombinant Drosha and DGCR8. Methods Mol. Biol. 2014; 1095: 73-86.