Manuel Ascano, Jr., Ph.D.

Associate Professor

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Faculty Appointments
Associate Professor of Biochemistry Associate Professor of Pathology, Microbiology and Immunology
Ph.D., Molecular Gen, Biochemistry, Microbiology, University of Cincinnati, Cincinnati, OhioB.S., Microbiology, University of Illinois, Urbana-Champaign, Illinois
Office Address
2215 Garland Avenue, 673C Light Hall
Nashville, TN 37232
Research Description
Aberrant RNA or DNA are robust triggers of the innate immune system as they can be early indicators of cellular damage or pathogenic infection by bacteria or virus. However, the criteria that could differentiate ‘self’ or ‘safe’ nucleic acids from ‘damaged’ or ‘foreign’ are not straightforward since the biochemical features of harmful RNA or DNA are not strictly unique to them. Viruses are particularly insidious as they have evolved strategies that either prevent their RNA or DNA genomes from being detected by pattern recognition receptors of the innate immune system and/or usurp specific machinery of cells in order to initiate viral replication. For example, owing to the rich tapestry of host RNA-binding proteins (RBPs) that facilitate cellular messenger RNA transcription, maturation, and translation, different RNA viruses have found ways to associate with cellular RBPs to exploit normal host RNA metabolic pathways in a manner that allows viral genomes to be processed, translated, and eventually replicated.

In an effort to understand the molecular arms race between host and pathogen, the research program of the Ascano laboratory is centered on exploring the mechanisms that cells use to differentiate whether a nucleic acid is derived from self or non-self, and the innate immune events that ensue following that decision point.

We have active research projects within two areas:

1) The roles and coordination of RNA-binding proteins in regulating gene expression during innate immune activation or viral infection.


2) The cytosolic DNA-sensing pathway involving the pattern recognition receptor and sensor cGAS, its second messenger product cGAMP, and the endoplasmic reticulum-bound receptor STING.

Our lab integrates novel biochemical, virological, immunological, and molecular and cell biological tools with high-throughput transcriptomic and proteomic technologies in an effort to elucidate the gene regulatory networks at play during immunologic stress. A deeper understanding of the physiological and pathological activities that surround RNA regulation enables us to leverage such information towards the development of novel vaccines and immunotherapeutics. The lab is affiliated with the Department of Biochemistry at the Vanderbilt University School of Medicine and is also part of the Microbe-Host Interactions Program within the Department of Pathology, Microbiology, and Immunology at VUMC.
Research Keywords
RNA, DNA, virus, host-pathogen interactions, biochemistry, innate immunity, post-transcriptional gene regulation
Rothamel K, Arcos S, Kim B, Reasoner C, Lisy S, Mukherjee N, Ascano M. ELAVL1 primarily couples mRNA stability with the 3' UTRs of interferon-stimulated genes. Cell Rep. 2021 May 5/25/2021; 35(8): 109178. PMID: 34038724, PMCID: PMC8225249, PII: S2211-1247(21)00523-4, DOI: 10.1016/j.celrep.2021.109178, ISSN: 2211-1247.

Kim B, Arcos S, Rothamel K, Ascano M. Viral crosslinking and solid-phase purification enables discovery of ribonucleoprotein complexes on incoming RNA virus genomes. Nat Protoc [print-electronic]. 2021 Jan; 16(1): 516-31. PMID: 33268883, PII: 10.1038/s41596-020-00429-6, DOI: 10.1038/s41596-020-00429-6, ISSN: 1750-2799.

Kim B, Arcos S, Rothamel K, Jian J, Rose KL, McDonald WH, Bian Y, Reasoner S, Barrows NJ, Bradrick S, Garcia-Blanco MA, Ascano M. Discovery of Widespread Host Protein Interactions with the Pre-replicated Genome of CHIKV Using VIR-CLASP. Mol Cell [print-electronic]. 2020 May 5/21/2020; 78(4): 624-640.e7. PMID: 32380061, PMCID: PMC7263428, PII: S1097-2765(20)30255-0, DOI: 10.1016/j.molcel.2020.04.013, ISSN: 1097-4164.

Wiser C, Kim B, Vincent J, Ascano M. Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells. Sci Rep. 2020 May 5/5/2020; 10(1): 7604. PMID: 32371942, PMCID: PMC7200739, PII: 10.1038/s41598-020-64348-y, DOI: 10.1038/s41598-020-64348-y, ISSN: 2045-2322.

Barrows NJ, Anglero-Rodriguez Y, Kim B, Jamison SF, Le Sommer C, McGee CE, Pearson JL, Dimopoulos G, Ascano M, Bradrick SS, Garcia-Blanco MA. Dual roles for the ER membrane protein complex in flavivirus infection: viral entry and protein biogenesis. Sci Rep. 2019 Jul 7/4/2019; 9(1): 9711. PMID: 31273220, PMCID: PMC6609633, PII: 10.1038/s41598-019-45910-9, DOI: 10.1038/s41598-019-45910-9, ISSN: 2045-2322.

Shae D, Becker KW, Christov P, Yun DS, Lytton-Jean AKR, Sevimli S, Ascano M, Kelley M, Johnson DB, Balko JM, Wilson JT. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy. Nat Nanotechnol [print-electronic]. 2019 Mar; 14(3): 269-78. PMID: 30664751, PMCID: PMC6402974, PII: 10.1038/s41565-018-0342-5, DOI: 10.1038/s41565-018-0342-5, ISSN: 1748-3395.

Wiser C, Kim B, Ascano M. G3BP1 enhances cytoplasmic DNA pattern recognition. Nat Immunol. 2019 Jan; 20(1): 5-7. PMID: 30538338, PII: 10.1038/s41590-018-0279-8, DOI: 10.1038/s41590-018-0279-8, ISSN: 1529-2916.

Mok-Lin E, Ascano M, Serganov A, Rosenwaks Z, Tuschl T, Williams Z. Premature recruitment of oocyte pool and increased mTOR activity in Fmr1 knockout mice and reversal of phenotype with rapamycin. Sci Rep. 2018 Jan 1/12/2018; 8(1): 588. PMID: 29330421, PMCID: PMC5766488, PII: 10.1038/s41598-017-18598-y, DOI: 10.1038/s41598-017-18598-y, ISSN: 2045-2322.

Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K, Gogakos T, Steinberg J, Reasoner S, Aso K, Tuschl T, Patel DJ, Glickman JF, Ascano M. Publisher Correction: Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun. 2017 Nov 11/23/2017; 8(1): 1827. PMID: 29170402, PMCID: PMC5700994, PII: 10.1038/s41467-017-01770-3, DOI: 10.1038/s41467-017-01770-3, ISSN: 2041-1723.

Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K, Gogakos T, Steinberg J, Reasoner S, Aso K, Tuschl T, Patel DJ, Glickman JF, Ascano M. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun. 2017 Sep 9/29/2017; 8(1): 750. PMID: 28963528, PMCID: PMC5622107, PII: 10.1038/s41467-017-00833-9, DOI: 10.1038/s41467-017-00833-9, ISSN: 2041-1723.

Kashima R, Roy S, Ascano M, Martinez-Cerdeno V, Ariza-Torres J, Kim S, Louie J, Lu Y, Leyton P, Bloch KD, Kornberg TB, Hagerman PJ, Hagerman R, Lagna G, Hata A. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. Sci Signal. 2016; 9(431): ra58. PMID: 27273096, PII: 9/431/ra58, DOI: 10.1126/scisignal.aaf6060, ISSN: 1937-9145.

Kavanaugh G, Zhao R, Guo Y, Mohni KN, Glick G, Lacy ME, Hutson MS, Ascano M, Cortez D. Enhancer of Rudimentary Homolog Affects the Replication Stress Response through Regulation of RNA Processing. Mol. Cell. Biol [print-electronic]. 2015 Sep 9/1/2015; 35(17): 2979-90. PMID: 26100022, PMCID: PMC4525316, PII: MCB.01276-14, DOI: 10.1128/MCB.01276-14, ISSN: 1098-5549.

Gao P, Zillinger T, Wang W, Ascano M, Dai P, Hartmann G, Tuschl T, Deng L, Barchet W, Patel DJ. Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA. Cell Rep [print-electronic]. 2014 Sep 9/25/2014; 8(6): 1668-76. PMID: 25199835, PMCID: PMC4381552, PII: S2211-1247(14)00673-1, DOI: 10.1016/j.celrep.2014.08.010, ISSN: 2211-1247.

Spitzer J, Hafner M, Landthaler M, Ascano M, Farazi T, Wardle G, Nusbaum J, Khorshid M, Burger L, Zavolan M, Tuschl T. PAR-CLIP (Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation): a step-by-step protocol to the transcriptome-wide identification of binding sites of RNA-binding proteins. Meth. Enzymol. 2014; 539: 113-61. PMID: 24581442, PMCID: PMC4180672, PII: B978-0-12-420120-0.00008-6, DOI: 10.1016/B978-0-12-420120-0.00008-6, ISSN: 1557-7988.

Wittkowski KM, Sonakya V, Bigio B, Tonn MK, Shic F, Ascano M, Nasca C, Gold-Von Simson G. A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism. Transl Psychiatry. 2014; 4: e354. PMID: 24473445, PMCID: PMC3905234, PII: tp2013124, DOI: 10.1038/tp.2013.124, ISSN: 2158-3188.

Gerstberger S, Hafner M, Ascano M, Tuschl T. Evolutionary conservation and expression of human RNA-binding proteins and their role in human genetic disease. Adv. Exp. Med. Biol. 2014; 825: 1-55. PMID: 25201102, PMCID: PMC4180674, DOI: 10.1007/978-1-4939-1221-6_1, ISSN: 0065-2598.

Gao P, Ascano M, Zillinger T, Wang W, Dai P, Serganov AA, Gaffney BL, Shuman S, Jones RA, Deng L, Hartmann G, Barchet W, Tuschl T, Patel DJ. Structure-function analysis of STING activation by c[G(2',5')pA(3',5')p] and targeting by antiviral DMXAA. Cell [print-electronic]. 2013 Aug 8/15/2013; 154(4): 748-62. PMID: 23910378, PMCID: PMC4386733, PII: S0092-8674(13)00894-5, DOI: 10.1016/j.cell.2013.07.023, ISSN: 1097-4172.

Nakanishi K, Ascano M, Gogakos T, Ishibe-Murakami S, Serganov AA, Briskin D, Morozov P, Tuschl T, Patel DJ. Eukaryote-specific insertion elements control human ARGONAUTE slicer activity. Cell Rep. 2013 Jun 6/27/2013; 3(6): 1893-900. PMID: 23809764, PMCID: PMC3757560, PII: S2211-1247(13)00288-X, DOI: 10.1016/j.celrep.2013.06.010, ISSN: 2211-1247.

Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, Serganov AA, Liu Y, Jones RA, Hartmann G, Tuschl T, Patel DJ. Cyclic [G(2',5')pA(3',5')p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell [print-electronic]. 2013 May 5/23/2013; 153(5): 1094-107. PMID: 23647843, PMCID: PMC4382009, PII: S0092-8674(13)00522-9, DOI: 10.1016/j.cell.2013.04.046, ISSN: 1097-4172.

Ascano M, Gerstberger S, Tuschl T. Multi-disciplinary methods to define RNA-protein interactions and regulatory networks. Curr. Opin. Genet. Dev [print-electronic]. 2013 Feb; 23(1): 20-8. PMID: 23453689, PMCID: PMC3624891, PII: S0959-437X(13)00011-7, DOI: 10.1016/j.gde.2013.01.003, ISSN: 1879-0380.

Ascano M, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, Langlois C, Munschauer M, Dewell S, Hafner M, Williams Z, Ohler U, Tuschl T. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature [print-electronic]. 2012 Dec 12/20/2012; 492(7429): 382-6. PMID: 23235829, PMCID: PMC3528815, PII: nature11737, DOI: 10.1038/nature11737, ISSN: 1476-4687.

Ascano M, Hafner M, Cekan P, Gerstberger S, Tuschl T. Identification of RNA-protein interaction networks using PAR-CLIP. Wiley Interdiscip Rev RNA [print-electronic]. 2012 Mar; 3(2): 159-77. PMID: 22213601, PMCID: PMC3711140, DOI: 10.1002/wrna.1103, ISSN: 1757-7012.

Hafner M, Ascano M, Tuschl T. New insights in the mechanism of microRNA-mediated target repression. Nature structural & molecular biology. 2011 Nov; 18(11) Sect. 1181,2.

Mukherjee N, Corcoran DL, Nusbaum JD, Reid DW, Georgiev S, Hafner M, Ascano M, Tuschl T, Ohler U, Keene JD. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol. Cell [print-electronic]. 2011 Aug 8/5/2011; 43(3): 327-39. PMID: 21723170, PMCID: PMC3220597, PII: S1097-2765(11)00421-7, DOI: 10.1016/j.molcel.2011.06.007, ISSN: 1097-4164.

Tian Y, Simanshu DK, Ascano M, Diaz-Avalos R, Park AY, Juranek SA, Rice WJ, Yin Q, Robinson CV, Tuschl T, Patel DJ. Multimeric assembly and biochemical characterization of the Trax-translin endonuclease complex. Nat. Struct. Mol. Biol [print-electronic]. 2011 Jun; 18(6): 658-64. PMID: 21552261, PMCID: PMC3109869, PII: nsmb.2069, DOI: 10.1038/nsmb.2069, ISSN: 1545-9985.

Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano M, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS, Dewell S, Zavolan M, Tuschl T. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell. 2010 Apr 4/2/2010; 141(1): 129-41. PMID: 20371350, PMCID: PMC2861495, PII: S0092-8674(10)00245-X, DOI: 10.1016/j.cell.2010.03.009, ISSN: 1097-4172.

Tokhunts R, Singh S, Chu T, D'Angelo G, Baubet V, Goetz JA, Huang Z, Yuan Z, Ascano M, Zavros Y, Thérond PP, Kunes S, Dahmane N, Robbins DJ. The full-length unprocessed hedgehog protein is an active signaling molecule. J. Biol. Chem [print-electronic]. 2010 Jan 1/22/2010; 285(4): 2562-8. PMID: 19920144, PMCID: PMC2807313, PII: M109.078626, DOI: 10.1074/jbc.M109.078626, ISSN: 1083-351X.

Hafner M, Landthaler M, Burger L, Khorshid M, Hausser J, Berninger P, Rothballer A, Ascano M, Jungkamp AC, Munschauer M, Ulrich A, Wardle GS, Dewell S, Zavolan M, Tuschl T. PAR-CliP--a method to identify transcriptome-wide the binding sites of RNA binding proteins. J Vis Exp. 2010; (41): PMID: 20644507, PMCID: PMC3156069, PII: 2034, DOI: 10.3791/2034, ISSN: 1940-087X.

Farzan SF, Stegman MA, Ogden SK, Ascano M, Black KE, Tacchelly O, Robbins DJ. A quantification of pathway components supports a novel model of Hedgehog signal transduction. J. Biol. Chem [print-electronic]. 2009 Oct 10/16/2009; 284(42): 28874-84. PMID: 19717563, PMCID: PMC2781433, PII: M109.041608, DOI: 10.1074/jbc.M109.041608, ISSN: 1083-351X.

Farzan SF, Ascano M, Ogden SK, Sanial M, Brigui A, Plessis A, Robbins DJ. Costal2 functions as a kinesin-like protein in the hedgehog signal transduction pathway. Curr. Biol [print-electronic]. 2008 Aug 8/26/2008; 18(16): 1215-20. PMID: 18691888, PMCID: PMC2774813, PII: S0960-9822(08)00893-2, DOI: 10.1016/j.cub.2008.07.026, ISSN: 0960-9822.

Ogden SK, Casso DJ, Ascano M, Yore MM, Kornberg TB, Robbins DJ. Smoothened regulates activator and repressor functions of Hedgehog signaling via two distinct mechanisms. J. Biol. Chem [print-electronic]. 2006 Mar 3/17/2006; 281(11): 7237-43. PMID: 16423832, PMCID: PMC3677211, PII: M510169200, DOI: 10.1074/jbc.M510169200, ISSN: 0021-9258.

Ascano M, Robbins DJ. An intramolecular association between two domains of the protein kinase Fused is necessary for Hedgehog signaling. Mol. Cell. Biol. 2004 Dec; 24(23): 10397-405. PMID: 15542847, PMCID: PMC529051, PII: 24/23/10397, DOI: 10.1128/MCB.24.23.10397-10405.2004, ISSN: 0270-7306.

Ogden SK, Ascano M, Stegman MA, Robbins DJ. Regulation of Hedgehog signaling: a complex story. Biochem. Pharmacol. 2004 Mar 3/1/2004; 67(5): 805-14. PMID: 15104233, PMCID: PMC3659400, ISSN: 0006-2952.

Stegman MA, Goetz JA, Ascano M, Ogden SK, Nybakken KE, Robbins DJ. The Kinesin-related protein Costal2 associates with membranes in a Hedgehog-sensitive, Smoothened-independent manner. J. Biol. Chem [print-electronic]. 2004 Feb 2/20/2004; 279(8): 7064-71. PMID: 14645371, PMCID: PMC3659396, PII: M311794200, DOI: 10.1074/jbc.M311794200, ISSN: 0021-9258.

Ogden SK, Ascano M, Stegman MA, Suber LM, Hooper JE, Robbins DJ. Identification of a functional interaction between the transmembrane protein Smoothened and the kinesin-related protein Costal2. Curr. Biol. 2003 Nov 11/11/2003; 13(22): 1998-2003. PMID: 14614827, PMCID: PMC3711143, PII: S0960982203007462, ISSN: 0960-9822.

Ascano M, Nybakken KE, Sosinski J, Stegman MA, Robbins DJ. The carboxyl-terminal domain of the protein kinase fused can function as a dominant inhibitor of hedgehog signaling. Mol. Cell. Biol. 2002 Mar; 22(5): 1555-66. PMID: 11839821, PMCID: PMC134684, ISSN: 0270-7306.

Mukhopadhyay B, Johnson EF, Ascano M. Conditions for vigorous growth on sulfide and reactor-scale cultivation protocols for the thermophilic green sulfur bacterium chlorobium tepidum. Appl. Environ. Microbiol. 1999 Jan; 65(1): 301-6. PMID: 9872796, PMCID: PMC91019, ISSN: 1098-5336.

Available Postdoctoral Position Details
Posted: 9/11/2014
A postdoctoral position in RNA Biochemistry and Molecular Biology is available in my laboratory. The postdoc will be joining a new research group whose primary research interests are in understanding the post-transcriptional gene regulatory mechanisms employed by cells during periods of innate immune activation and cellular stress. The Ascano laboratory integrates traditional biochemistry, cell biology, and molecular biological disciplines with modern high-throughput and bioinformatics-oriented methodologies. Available research projects focus either on the delineation and functional characterization of specific RNA-protein interaction networks or on the biochemical dissection of a newly identified nucleic acid-stimulated innate immune signaling pathway. Interested candidates should submit by email a single PDF containing a cover letter, a CV with contact information for three references, and a very brief summary (1 page) of research accomplishments and potential research interests in my lab.