Enzymatic DNA deamination and the immunity/cancer balance

Información del proyecto

APOBEC

Identificador del acuerdo de subvención: 660883

DOI

10.3030/660883

Proyecto finalizado el 12 Octubre 2017

Fecha de la firma de la CE 17 Marzo 2015

Fecha de inicio 1 Abril 2015

Fecha de finalización 31 Marzo 2017

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 159 460,80

Aportación de la UE

€ 159 460,80

Coordinado por

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Germany

Periodic Reporting for period 1 - APOBEC (Enzymatic DNA deamination and the immunity/cancer balance)

Período documentado: 2015-04-01 hasta 2017-03-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

see above

Figure-4 from Sander et al, Immunity 2015