DNA polymerase mu, a candidate hypermutase?

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Abstract
A novel DNA polymerase (Pol μ) has been recently identified in human cells. The amino–acid sequence of Pol μ is 42% identical to that of terminal deoxynucleotidyl transferase (TdT), a DNA–independent DNA polymerase that contributes to antigen–receptor diversity. In this paper we review the evidence supporting the role of Pol μ 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 associated to developing germinal centres; and (iii) very low base discrimination during DNA–dependent DNA polymerization by Pol μ, 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 β) with DNA, allows us to discuss the structural basis for the unprecedented error proneness of Pol μ, and to predict that Pol μ is structurally well suited to participate also in DNA end–filling steps occurring both during V(D)J recombination and repair of DNA double–strand breaks that are processed by non–homologous end–joining.