DNA polymerase mu, a candidate hypermutase?

A novel DNA polymerase (Pol mu) has been recently identified in human cells . The amino-acid sequence of Pol mu is 42% identical to that of terminal de oxynucleotidyl transferase (TdT), a DNA-independent DNA polymerase that con tributes to antigen-receptor diversity. In this paper we review the evidenc e supporting the role of Pol mu in somatic hypermutation of immunoglobulin genes, a T-dependent process that selectively occurs at germinal centres: ( i) preferential expression in secondary lymphoid organs; (ii) expression as sociated to developing germinal centres; and (iii) very low base discrimina tion during DNA-dependent DNA polymerization by Pol mu, a mutator phenotype enormously accentuated by the presence of activating Mn2+ ions. Moreover, its similarity to TdT, together with extrapolation to the crystal structure of DNA polymerase beta complexed (Pol beta) with DNA, allows us to discuss the structural basis for the unprecedented error proneness of Pol mu, and to predict that Pol mu is structurally well suited to participate also in D NA end-filling steps occurring both during V (D)J recombination and repair of DNA double-strand breaks that are processed by non-homologous end-joinin g.