Periodic Reporting for period 1 - APOBEC (Enzymatic DNA deamination and the immunity/cancer balance)
Reporting period: 2015-04-01 to 2017-03-31
The problem originally addressed in the project in the frame of the Marie Curie program related to the role of the APOBEC family of DNA deaminating enzymes in the generation of somatic antibody diversity, control of viral infection and lymphomagenesis. All these issues are central for human health and disease and therefore of great importance for society.
The original objectives of the proposal were to
1) determine the contribution of APOBEC3 catalytic activity to genomic instability
2) understand the mechanism of kataegis (a special category of extensive localized mutagenesis) and the regulation of human APOBEC enzymes
3) delineate the requirement for aberrant AID activity in inflammation-associated carcinogenesis.
The original objectives of the proposal were to
1) determine the contribution of APOBEC3 catalytic activity to genomic instability
2) understand the mechanism of kataegis (a special category of extensive localized mutagenesis) and the regulation of human APOBEC enzymes
3) delineate the requirement for aberrant AID activity in inflammation-associated carcinogenesis.
For various reasons, the project developed not exactly along the lines of the original proposal. The critical mouse line for the project, namely mice expressing human APOBEC3b conditionally upon induction, turned out to be incorrectly targeted and had to be regenerated at the MDC (work in progress). During this process, Dr. Franklin played a decisive role in the analysis of the role of a transcription factor, FOXO1, as a master regulator in the control of the germinal center reaction Dark Zone, where antigen-activated B cells undergo somatic hypermutation in response to antigen stimulation and are selected to become high-affinity antigen binding cells. He also initiated an investigation into the structure of the enzyme mediating somatic hypermutation, AID, and began to analyze the role of FOXO1 in controlling the synapsis of switch regions in mediating antibody class switch recombination. He also played a critical role in the finalization of a publication demonstrating the integration of signals through the B cell antigen receptor with Toll-like receptors controlling B cell proliferation in the B cell response to pathogens. Two publications in high-ranking journals have resulted from these efforts (Sander et al. Immunity 2015; Otipoby et al. PNAS 2015), and experimental work along the lines of the original proposal are ongoing.