title: Checkpoint kinase 1 negatively regulates somatic hypermutation.
abstract: Immunoglobulin (Ig) diversification by somatic hypermutation in germinal center B cells is instrumental for maturation of the humoral immune response, but also bears the risk of excessive or aberrant genetic changes. Thus, introduction of DNA damage by activation-induced cytidine deaminase as well as DNA repair by multiple pathways need to be tightly regulated during the germinal center response to prevent lymphomagenesis. In the present study, we show that DNA damage checkpoint signaling via checkpoint kinase 1 (Chk1) negatively regulates somatic hypermutation. Chk1 inhibition in human B cell lymphoma lines as well as inactivation of Chk1 alleles by gene targeting in DT40 B cells leads to increased somatic hypermutation. This is apparently due to changes in DNA repair pathways regulated by Chk1, such as a decreased homologous recombination efficiency that also leads to decreased Ig gene conversion in DT40. Our data show that Chk1 signaling plays a crucial role in regulation of Ig diversification and sheds unexpected light on potential origins of aberrant somatic hypermutation in B cell lymphomagenesis.
authors.affiliation: Institute of Clinical and Molecular Biology, Helmholtz Center Munich, Marchioninistrasse 25, 81377 Munich, Germany, Department of Cell Biology, Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich-Schiller University Jena, Hans-Knoell-Strasse 2, 07745 Jena, Germany and Department of Gene Vectors, Helmholtz Center Munich, Marchioninistrasse 25, 81377 Munich, Germany.
authors.forename: Samantha
authors.initials: S
authors.lastname: Frankenberger
authors.forename: Kathrin
authors.initials: K
authors.lastname: Davari
authors.forename: Sabine
authors.initials: S
authors.lastname: Fischer-Burkart
authors.forename: Katrin
authors.initials: K
authors.lastname: Böttcher
authors.forename: Nils-Sebastian
authors.initials: NS
authors.lastname: Tomi
authors.forename: Ursula
authors.initials: U
authors.lastname: Zimber-Strobl
authors.forename: Berit
authors.initials: B
authors.lastname: Jungnickel
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004260:DNA Repair; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse