Uttiya Basu, Ph.D.
Associate Professor of Microbiology & Immunology
Ph.D., Albert Einstein College of Medicine
RNA surveillance, noncoding RNA processing and DNA alteration events in lymphocytes
Our studies have led to the unexpected conclusion that a significant portion of the mammalian genome transcribes noncoding RNAs (ncRNAs) and that the RNA exosome, a component of the cellular ncRNA surveillance machinery, rapidly decays some of the ensuing ncRNAs. Two questions have arisen: is there a biological function of ncRNA decay of such large and unprecedented nature, and what are the pathophysiological consequences of failure of ncRNA decay? Using B-lymphocytes as a model system, our laboratory has pioneered studies demonstrating that surveillance and decay of the ncRNA transcriptome is an important mechanism for development and function of mammalian cells and when compromised, causes genomic instability, immune system dysregulation, and genetic alterations specific to cancer initiation.
In normal conditions, RNA surveillance pathway components orchestrate programmed immunoglobulin locus recombination by facilitating access of the DNA mutator AID to single strand DNA sequences stripped of inhibitory ncRNAs. Thus, our study provides the first evidence that RNA-decay machinery can be specifically targeted to a particular region of the mammalian genome to facilitate a defined biological function.
We discovered that when RNA surveillance pathways are suppressed by various genetic mutations, transcription associated DNA/RNA hybrids are not efficiently unwound leading to DNA mutagenesis and translocations. In pathophysiological conditions like in lymphomagenesis the RNA exosome subunit and cofactors are mutated; likewise, the developmental defects leading to Pontocerebellar Hypoplasia are caused by restricted ncRNA decay mediated by RNA exosome. Thus, our current studies highlight the relationship of RNA surveillance and transcription associated DNA mutagenesis in human diseases related to the immune and nervous systems.
Leeman-Neill, R.J., Lim, J. and Basu, U. (2018) The common key to class-switch recombination and somatic hypermutation: discovery of AID and its role in antibody gene diversification. J. Immunol. 201: 2527-2529.
Lim, J., Giri, P.K., Kazadi, D., Laffleur, B., Zhang, W., Grinstein, V., Pefanis, E., Brown, L.M., Ladewig, E., Martin, O., Chen, Y., Rabadan, R., Boyer, F., Rothschild, G., Cogne, M., Pinaud, E., Deng, H. and Basu, U. (2017) Nuclear proximity of Mtr4 to RNA exosome restricts DNA mutational asymmetry. Cell 169: 523-537 e515.
Rialdi, A., Hultquist, J., Jimenez-Morales, D., Peralta, Z., Campisi, L., Fenouil, R., Moshkina, N., Wang, Z.Z., Laffleur, B., Kaake, R.M., McGregor, M.J., Haas, K., Pefanis, E., Albrecht, R.A., Pache, L., Chanda, S., Jen, J., Ochando, J., Byun, M., Basu, U., Garcia-Sastre, A., Krogan, N., van Bakel, H. and Marazzi, I. (2017) The RNA exosome syncs IAV-RNAPII transcription to promote viral ribogenesis and infectivity. Cell 169: 679-692 e614.
Rothschild, G. and Basu, U. (2017) Lingering questions about enhancer RNA and enhancer transcription-coupled genomic instability. Trends Genet. 33: 143-154.
Laffleur, B., Basu, U. and Lim, J. (2017) RNA exosome and non-coding RNA-coupled mechanisms in AID-mediated genomic alterations. J. Mol. Biol. pii: S0022-2836(17)30012-8. doi: 10.1016/j.jmb.2016.12.021. [Epub ahead of print]
Casellas, R., Basu, U., Yewdell, W.T., Chaudhuri, J., Robbiani, D.F. and Di Noia, J.M. (2016) Mutations, kataegis and translocations in B cells: understanding AID promiscuous activity. Nature Rev. Immunol. 16: 164-176.
Sun J., Wang J., Pefanis E., Chao J., Rothschild G., Tachibana I., Chen J., Ivanov I.I., Rabadan R., Takeda Y. and Basu U. (2015) Transcriptomics identify CD9 as a marker of murine IL-10 competent regulatory B cells. Cell Reports 13: 1110-1117.
Rothschild G., Von Krusenstiern, A.N. and Basu U. (2015) Malaria-induced B cell genomic instability. Cell 162: 697-698.
Pefanis E. and Basu U. (2015) RNA exosome regulates AID DNA mutator activity in the B cell genome. Advances in Immunology 127: 257-308.
Pefanis E., Wang J., Rothschild G., Lim J., Kazadi D., Sun J., Federation A., Chao J., Elliot O., Liu Z-P., Economides A., Bradner J.E., Rabadan R. and Basu U. (2015) RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity. Cell 161: 774-789.
Pefanis, E., Wang, J., Rothschild, G., Lim, J., Chao, J., Rabadan, R., Economides, A.N. and Basu, U. (2014) Noncoding RNA transcription targets AID to divergently transcribed loci in B cells. Nature 514: 389-393.
Chao, J., Rothschild, G. and Basu, U. (2014) Ubiquitination events that regulate recombination of immunoglobulin Loci gene segments. Front. Immunol. 5: 100. doi: 10.3389/fimmu.2014.00100.
Sun, J., Keim, C.D., Wang, J., Kazadi, D., Oliver, P.M., Rabadan, R., and Basu, U. (2013) E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells. Genes Dev. 27: 1821-1833.
Sun, J., Rothschild, G., Pefanis, E., and Basu, U. (2013) Transcriptional stalling in B-lymphocytes: A mechanism for antibody diversification and maintenance of genomic integrity. Transcription. 4: 127-135.
Keim, C., Kazadi, D., Rothschild, G. and Basu, U. (2013) Regulation of AID, the B-cell Genome Mutator. Genes Dev. 27: 1-17.
Basu, U.*, Meng, F.L., Keim, C., Grinstein, V., Pefanis, E., Eccleston, J., Zhang, T., Myers, D., Wasserman, C.R., Wesemann, D.R., Januszyk, K., Gregory, R.I., Deng, H., Lima, C.D. and Alt. F.W.*. (2011) The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 144: 353-363. (*corresponding authors)
Ise, W., Kohyama, M., Schraml, B.U., Zhang, T., Schwer, B., Basu, U., Alt, F.W., Tang, J., Oltz, E.M., Murphy, T.L. and Murphy, K.M. (2011) The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nature Immunology 12:536-543.
Basu, U., Franklin, A., Schwer, B., Cheng, H-L, Chaudhuri, J. and Alt, F.W. (2009) Regulation of Activation-Induced Cytidine Deaminse DNA Deamination Activity in B cell by Serine-38 phosphorylation. Biochem. Soc. Trans. 37: 561-568.
Cheng, H.L., Vuong, B., Basu, U., Franklin, A., Schwer, B., Phan, R., Datta, A., Manis, J., Alt, F.W. and Chaudhuri, J. (2009) Integrity of the AID Serine-38 Phosphorylation Site is Critical for Class Switch Recombination and Somatic Hypermutation in Mice. Proc. Natl. Acad. Sci. U.S.A.106: 2717-2722.
Basu, U., Franklin, A. and Alt, F.W. Post-translational regulation of activation induced deaminase. (2009) Philosophical Transactions of the Royal Society of Sciences 364: 667-673.
Basu, U., Wang, Y., Alt, F.W. (2008) Evolution of phosphorylation-dependent regulation of Activation Induced cytidine Deaminase. Molecular Cell 32: 285-291.
Chaudhuri, J., Basu, U., Zarrin, A., Yan, C., Franco, S., Perlot, T., Vuong, B., Wang, J., Phan, R.T., Datta, A., Manis, J., and Alt, F.W. (2007) Evolution of the Immunoglobin Heavy Chain Class Switch Recombination Mechanism. Advances in Immunology 94: 157-214.
Basu, U., Chaudhuri, J., Phan, R.T., Datta, A. and Alt, F.W. (2007) Regulation of activation induced deaminase via phosphorylation In: Mechanisms of Lymphocyte Activation and Immune Regulation XI, Gupta, S., Cooper, M., Rajewsky, K., Alt, F.W., Melchers, F., Eds. New York, Springer, 129-137.
Longerich, S., Basu, U., Alt, F.W. and Storb, U. (2006) AID in somatic hypermutation and class switch recombination. Curr. Op. In Immunology 18: 1-11.
Basu, U., Chaudhuri, J., Alpert, C., Dutt, S., Rangananth, S., Li, G., Schrum, J.P., Manis, J.P. and Alt, F.W. (2005) The AID antibody diversification enzme is regulated by protein kinase A phosphorylation. Nature 438: 508-511.