AID Targeted to Both DNA Strands by RNA Exosome:
A Role for Non-coding RNA Surveillance Machinery in Antibody Diversity
Uttiya Basu, Assistant Professor of Microbiology & Immunology
Antigens that can elicit an immune response are almost
infinite in number. However, there are only a very finite
number of genes at our disposal to synthesize antibodies
specific for each of these potentially harmful antigens. B
lymphocytes resolve this seemingly insurmountable challenge
by undergoing three impressive processes, each making
a powerful contribution to the organism's ability to fend
off attacks by potential pathogens.
First, immature B lymphocytes in the bone marrow undergo
V(D)J recombination, which dramatically increases the immunoglobulin
(Ig) repertoire of the organism. Then, these B
cells migrate to secondary lymphoid organs, where they go
through somatic hypermutation to increase the affinity of
an immunoglobulin for the epitope it binds. Finally, they
undergo class switch recombination (CSR) to diversify and
best tailor the kind of effector function that results from
interacting with an antigen. These last two genetic alterations,
which establish antibody memory, absolutely require
the activity of the ssDNA cytidine deaminase AID.
It is imperative to understand the mechanism of function of
AID, since loss of AID activity leads to immune-deficiencies
known as hyper IgM-syndrome, whereas hyper-AID activity
initiates aberrant chromosomal lesions and translocations
that lead to oncogenesis. In this regard, most B cell lymphomas
are caused by chromosomal translocations of the
Ig locus that lead to deregulated expression of protooncogenes.
Furthermore, a large number of germinal center
derived B-cell lymphomas are associated with hypermutation
of proto-oncogenes at signature AID substrate motifs.
Although the importance of AID as a key regulator of
adaptive immunity and potential oncogene is well established,
the molecular mechanism by which AID performs its
function is not completely understood. How AID identifies
its physiological target sequences in the B cell genome and
imparts mutations on DNA is an active area of investigation.
In our recently published work we have implicated the cellular
non-coding RNA-processing/degradation complex, RNA
exosome, in targeting AID to both DNA strands. In B cells
activated for CSR, the RNA exosome associates with AID,
accumulates on IgH switch regions and promotes optimal
CSR. Moreover purified RNA exosome complex imparts robust
AID- and transcription-dependent DNA deamination of
both strands of transcribed DNA substrates in vitro, thus
providing vital mechanistic insight into molecular mechanism
of AID action. Our findings reveal a role for noncoding
RNA surveillance machinery in generating antibody
diversity. Future work will focus on the role of non-coding
RNAs and RNA exosome complex during generation of
adaptive immune response using various mouse model
- 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., 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)
Recent Notable Faculty Publications
- Minc, N., Burgess, D. and Chang, F. (2011) Influence of Cell Geometry on Division-Plane Positioning. Cell 144: 414-426. (A Cell Research Highlight)
- Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L.H., Lerach, S., Tang, H., Ma, J., Rossi, D., Chadburn, A., Murty, V.V., Mullighan, C.G., Gaidano, G., Rabadan, R., Brindle, P.K. and Dalla-Favera, R. (2011) Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471: 189-195.
- Laaberki, M-H., Pfeffer, J., Clarke, A. and Dworkin J. (2011) O-acetylation of peptidoglycan is required for proper cell separation and S-layer anchoring in Bacillus anthracis. J. Biol Chem 286: 5278-5288.
- Adjalley, S.H., Johnston, G.L., Li, T., Eastman, R.T., Ekland, E.H., Eappen, A.G., Richman, A., Sim, B.K., Lee, M.C., Hoffman, S.L. and Fidock, D.A. (2011) Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue. Proc. Natl. Acad. Sci. U.S.A. Epub ahead of print 2011 Oct 31.
- West, A.P., Brodsky, I.E., Rahner, C., Woo, D.K., Erdjument-Bromage, H., Tempst, P., Walsh, M.C., Choi, Y., Shadel, G.S. and Ghosh, S. (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472: 476-480.
- Arriagada, G., Muntean, L.N. and Goff, S.P. (2011) SUMO-interacting motifs of human TRIM5alpha are important for antiviral activity. PLoS Pathog. 7:e1002019. Epub 2011 Apr 7.
- Washburn, R.S. and Gottesman, M.E. (2011) Transcription termination maintains chromosome integrity. Proc. Natl. Acad. Sci. U.S.A. 108: 792-797.
- Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., Cheng, G., Yamasaki, S., Saito, T., Ohba, Y., Taniguchi, T., Takeda, K., Hori, S., Ivanov, I.I., Umesaki, Y., Itoh, K. and Honda, K. (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331: 337-341.
- Klein, U. and Ghosh, S. (2011) The two faces of NF-kB signaling in cancer development and therapy. Cancer Cell. 20: 556-558.
- Anandasabapathy, N., Victora, G.D., Meredith, M., Feder, R., Dong, B., Kluger, C., Yao, K., Dustin, M.L., Nussenzweig, M.C., Steinman, R.M. and Liu, K. (2011) Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain.J. Exp. Med. 208: 1695-1705. Epub 2011 Jul 25.
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- Chang, J.T., Ciocca, M.L., Kinjyo, I., Palanivel, V.R., McClurkin, C.E., Dejong, C.S., Mooney, E.C., Kim, J.S., Steinel, N.C., Oliaro, J., Yin, C.C., Florea, B.I., Overkleeft, H.S., Berg, L.J., Russell, S.M., Koretzky, G.A., Jordan, M.S. and Reiner, S.L. (2011) Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division. Immunity 34: 492-504. Epub 2011 Apr 14.
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Graphical abstract highlighting targeting of AID to
both strands of DNA by the RNA exosome cellular RNA processing/