Multiple functions of MRN in end-joining pathways during isotype class switching

The Mre11/Rad50/NBS1 (MRN) complex plays many roles in response to DNA double strand breaks (DSBs), but its functions in repair by non homologous end joining (NHEJ) pathways are poorly understood. We have investigated requirements for MRN in Class Switch Recombination (CSR), a programmed DNA rearrangement in B lymphocytes that requires NHEJ. To this end we have engineered mice that lack the entire MRN complex in B lymphocytes, or possess an intact complex harboring mutant Mre11 lacking DNA nuclease activities. MRN deficiency confers a striking defect in CSR, impacting both the Classic and Alternative NHEJ pathways. In contrast, absence of Mre11 nuclease activities causes a milder phenotype, revealing a separation of function within the complex. We propose a model in which MRN stabilizes distant breaks and processes DNA termini to facilitate repair by both the Classical and Alternative NHEJ pathways.