Analysis of the Function of DNA Polymerase Kappa and M17 in the Immune System

Schenten, Dominik (2003). Analysis of the Function of DNA Polymerase Kappa and M17 in the Immune System. PhD thesis, Universität zu Köln. Open Access

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Abstract

In T cell-dependent immune responses, activated B cells undergo a phase of rapid expansion and form distinct histological structures, the germinal centers (GC). GCs are the sites of secondary antibody diversification. Somatic hypermutation (SHM) introduces mutations into the rearranged V genes, whereas class switch recombination (CSR) alters the IgH constant region to modulate effector function. The current model of SHM postulates cytidine deamination by AID, followed by error-prone repair that involves short-patch DNA synthesis by error-prone DNA polymerases. The Pol k (DinB1) gene encodes a specialized mammalian DNA polymerase called DNA polymerase k. The mouse Pol k gene is expressed in most tissues of the body including B cells. The ability of Pol k to generate mutations when extending primers on undamaged DNA templates identifies this enzyme as a candidate for the introduction of nucleotide exchanges during SHM. Here, I show that Polk-deficient mice are viable, fertile and able to mount a normal immune response to the antigen (4-hydroxy-3-nitrophenyl) acetyl-chicken globulin (NPGC). Polk-deficient mice mutate their Ig genes normally. Pol k-/- Pol l-/- Pol i-/- mice also show no defects in SHM, indicating that these error-prone DNA polymerases do not substitute for each other's function during SHM. However, Polk-deficient embryonic fibroblasts are sensitive to cell death following exposure to ultraviolet radiation, suggesting a role for Polk in translesion DNA synthesis. The human gene HGAL serves as marker in the prognosis of patients with GC-derived diffuse large B cell lymphomas (DLBCL). The mouse gene M17 is the homologue of HGAL. M17 is predominantly expressed in the GCs, indicating a role in GC function. In the present study, I analyzed M17-/- mice to investigate the role of M17 in the GC reaction. M17-/- mice form normal GCs, undergo efficient CSR and SHM and mount a T cell-dependent immune response. Thus, M17 is dispensable for the GC reaction and the current data support a rather indirect role for HGAL as a prognostic marker in the biology of DLBCL.

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Thesis (PhD thesis)

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