Transcription, beta-like DNA polymerases and hypermutation

This paper discusses two aspects of immunoglobulin (Ig) gene hypermutation. In the first approach, a transcription termination signal is introduced in an Ig light chain transgene acting as a mutation substrate, and transgenic lines are generated with control and mutant transgenes integrated in tande m. Analysis of transcription levels and mutation frequencies between mutant and control transgenes clearly dissociates transcription elongation and mu tation, and therefore argues against models whereby specific pausing of the RNA polymerase during V gene transcription would trigger an error-prone re pair process. The second part reports the identification of two novel beta -like DNA polymerases named Pol lambda and Pol mu, one of which (Pol mu) re presents a good candidate for the Ig mutase due to its higher lymphoid expr ession and its similarity with the lymphoid enzyme terminal deoxynucleotidy l transferase. Peculiar features of the expression of this gene, including an unusual splicing variability and a splicing inhibition in response to DN A-damaging agents, are discussed.