Mechanisms by which transcription can regulate somatic hypermutation.

Abstract

Mechanisms for somatic hypermutation (SHM) have proven elusive. An actively transcribed substrate was analyzed to elucidate the role of stem-loop structures (SLSs) in SHM. Analysis with a new computer algorithm indicates that the location and mutability of a base are regulated by: (a) the extent to which it is unpaired, (b) the degree to which it is exposed by stabilization of SLSs containing and flanking it, and (c) the level of transcription that drives supercoiling, which creates and stabilizes SLSs containing unpaired bases vulnerable to mutation. New mechanisms are described by which transcription can differentially stabilize SLSs harboring targeted bases and establish specific base exposure patterns. Assuming that transcription levels correlate with the magnitude of superhelicity induced and the lengths of ssDNA forming SLSs, this analysis accounts for the location of all mutable bases during SHM.