ADN polimerasa mu (Pol µ), una enzima implicada en reparación y variabilidad del ADN
Author
Ruiz Pérez, Jose F.Advisor
Blanco Dávila, LuisEntity
UAM. Departamento de Biología MolecularDate
2004-04-23Subjects
ADN polimerasas - Tesis doctorales; ADN - Reparación - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular, Fecha de lectura 23-04-2004Abstract
Identification and characterization of human DNA polymerase mu (Pol µ), a novel family X DNA polymerase, is described in this work. This enzyme shares 42% amino acid identity with terminal deoxynucleotidyltransferase (TdT), a template independent DNA polymerase that contributes to the diversification of antigen receptor genes. Human recombinant Pol µ was purified near to homogeneity, and in vitro polymerization assays demonstrated that displays intrinsic terminal transferase activity, although its polymerization efficiency is strongly enhanced by the presence of a template strand. Biochemical studies of purified human Pol p have shown a unique property that has never been observed with any other polymerases: Pol µ displays a strong tendency to accept/induce transient template misalignments during DNA synthesis. Moreover, Pol µ can promote primer-template realignments, achieving microhomology search and microhomology pairing. These data suggest that Pol µ could have an important role in the end-joining pathway for repair of DNA double strand breaks. On the other hand, the unusual capacity of Pol µ to promote transient primer-template misalignments in vitro frequently results in an error-prone DNA synthesis. These biochemical data and the preferential Pol µ expression pattern at second lymphoid tissues suggest that Pol µ could be a good candidate to be one of the putatives mutator DNA polymerases involved in somatic hypermutation of immunoglobulin genes, a process that contributes to the diversification of immunoglobulins and selectively occurs at secondary lymphoid tissues. To demonstrate this, human Pol µ was overproduced in a lymphoid B cell line (Ramos) that undergoes hypermutation constitutively and the mutational rates of the Ig genes was analyzed. Interestingly, Ramos cells overproducing human Pol µ showed a 3-fold increase of somatic mutations specifically targeted to their immunoglobulin variable genes.
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