Altered class switch recombination junctions in patients with deficiency in Mlh1 and Brca1 (109.6)

Abstract

Abstract Class switch recombination (CSR) is a B-cell specific process that results in the change of immunoglobulin isotype from IgM to IgA, IgG or IgE. It involves the creation of DNA double strand breaks (DSBs) in switch regions, which are sensed and repaired by DNA damage response proteins and the non-homologous end-joining (NHEJ) pathway. Here we have studied CSR in patients with heterozygous mutations in both the mismatch repair (MMR) gene Mlh1 and the breast cancer susceptibility gene Brca1 and in patients with mutations in either Mlh1 or Brca1 alone. Brca1 is involved in several processes ranging from DNA DSB repair, particularly through homologous recombination, and cell cycle checkpoint control to ubiquitination and chromatin remodeling. Its function in NHEJ as well as in CSR is unknown. The MMR pathway normally repairs mismatches arising in the DNA, while during CSR it seems to be involved in the creation of DSBs by processing of mismatches in the switch regions. To study CSR in the patients we have analyzed the in vivo generated recombination switch junctions, formed after the repair of two switch regions during CSR. We have found that the switch recombination junctions are altered in all patients, suggesting the importance of these proteins during CSR in human B cells.