Heads of Laboratories
DNA diversification processes are widely used to diversify cellular proteomes, for example to generate antibodies against pathogen entry. Many pathogens have evolved similar mechanisms to alter their surface antigens, thereby evading the antibody response. Cells and organisms have also evolved to alter their RNA with specific outcomes such as genetic code recoding or gene expression reprogramming. Dr. Papavasiliou’s research focuses on the different molecular processes that cells and organisms employ to diversify and expand the information encoded in their genomes.
Using a combination of biochemistry and genetics, Dr. Papavasiliou is studying the molecular basis of the specific type of DNA mutation that underlies the diversification of antibodies in the B lymphocytes of the immune system. When B cells, specialized cells that produce antibodies against foreign molecules, encounter an antigen, mutations are introduced in the genes of their B cell receptors that recognize that antigen. This hypermutation process helps some of those B cells to acquire a higher affinity for the antigen, and those cells then become selected for survival; i.e., the immune system selects the B cells that are the best candidates for long-term memory against the antigen. Without somatic hypermutation, an individual may become immunocompromised in the ability to deal with antigens.
Hypermutation in B cells is dependent on a protein called activation-induced cytidine deaminase (AID). When AID is expressed in these cells, it changes cytidine residues in the DNA to uracil, which is then recognized as DNA damage. Normally, the cell repairs uracil lesions by properly converting them back to cytidine; somehow, in B cells, the damaged antibody genes are misrepaired, such that the uracil lesion is converted to thymidine. How AID targets antibody genes for deamination and why uracil lesions in antibody genes are misrepaired, even though they are properly repaired in all other contexts, are questions under investigation in the Papavasiliou lab.
B cells use DNA mutation to diversify and expand their antibody repertoire, which they need to block entry and eventually remove pathogens. Other organisms use DNA recombination to diversify their surface receptors and specifically evade antibody recognition. For instance, surface antigen variation in parasites like the African trypanosome (Trypanosoma brucei, the causative agent of sleeping sickness) is generated by gene conversion between silent cassettes and one active expression site. Understanding the mechanism that initiates targeted gene conversion in these parasites is an active area of interest in the lab (and an ongoing collaboration with Rockefeller’s George A.M. Cross).
AID belongs to the AID/APOBEC family of cytidine deaminase enzymes, most of which deaminate DNA to initiate DNA mutation. One of these, however, the APOBEC-1 deaminase, functions not as a DNA mutator but as an RNA “editor.” Using transcriptome-wide binary comparisons between a genomic DNA sequence and the sequence of its RNA transcript, the Papavasiliou lab has uncovered multiple instances of APOBEC-1 editing that resulted in C-to-U changes in the edited transcript (noted as C-to-T differences between genomic DNA and messenger RNA), which effectively reprogram gene expression. The lab is keenly interested in further understanding the functional relevance of these changes at the organismal level.
Finally, these genome/transcriptome comparisons have revealed a multitude of RNA/DNA alterations that occur at high frequency but cannot be attributed to cytidine deamination. These occur both in coding regions and in regulatory regions, and the lab is currently devising methods to first catalog these and to then characterize them functionally. Altogether, these preliminary findings reveal an extraordinary level of informational plasticity in biological systems.
Originally from Greece, Dr. Papavasiliou received her undergraduate degree in biology, with a minor in German literature, from Oberlin College in 1992. She completed her Ph.D. in molecular immunology in 1998 at The Rockefeller University. After postdoctoral studies at Yale University, Dr. Papavasiliou returned to Rockefeller as assistant professor in 2001, becoming associate professor in 2007.
In 2005 Dr. Papavasiliou received the Alexandrine and Alexander L. Sinsheimer Fund Scholar Award. She is a 2003 Searle Scholar and a 2002 Keck Fellow.
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