title: Lack of MSH2 involvement differentiates V(D)J recombination from other non-homologous end joining events.
abstract: V(D)J recombination and class switch recombination are the two DNA rearrangement events used to diversify the mouse and human antibody repertoires. While their double strand breaks (DSBs) are initiated by different mechanisms, both processes use non-homologous end joining (NHEJ) in the repair phase. DNA mismatch repair elements (MSH2/MSH6) have been implicated in the repair of class switch junctions as well as other DNA DSBs that proceed through NHEJ. MSH2 has also been implicated in the regulation of factors such as ATM and the MRN (Mre11, Rad50, Nbs1) complex, which are involved in V(D)J recombination. These findings led us to examine the role of MSH2 in V(D)J repair. Using MSH2-/- and MSH2+/+ mice and cell lines, we show here that all pathways involving MSH2 are dispensable for the generation of an intact pre-immune repertoire by V(D)J recombination. In contrast to switch junctions and other DSBs, the usage of terminal homology in V(D)J junctions is not influenced by MSH2. Thus, whether the repair complex for V(D)J recombination is of a canonical NHEJ type or a separate microhomology-mediated-end joining (MMEJ) type, it does not involve MSH2. This highlights a distinction between the repair of V(D)J recombination and other NHEJ reactions.
authors.affiliation: Department of Immunology, University of Toronto, Medical Sciences Building 5265, Toronto, Canada, M5S 1A8. mani.larijani@utoronto.ca
authors.forename: Mani
authors.initials: M
authors.lastname: Larijani
authors.forename: Ahmad
authors.initials: A
authors.lastname: Zaheen
authors.forename: Darina
authors.initials: D
authors.lastname: Frieder
authors.forename: Yuxun
authors.initials: Y
authors.lastname: Wang
authors.forename: Gillian E
authors.initials: GE
authors.lastname: Wu
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000276:immunology; D002460:Cell Line; D004260:DNA Repair; D015322:Gene Rearrangement, B-Lymphocyte; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000502:physiology*; D011995:Recombination, Genetic
chemical_list: D007128:Immunoglobulin Fragments; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein