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Frankenberger, S. ; Davari, K.* ; Fischer-Burkart, S. ; Böttcher, K.* ; Tomi, N.S.* ; Zimber-Strobl, U. ; Jungnickel, B.

Checkpoint kinase 1 negatively regulates somatic hypermutation.

Nucleic Acids Res. 42, 3666-3674 (2014)
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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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Induced Cytidine Deaminase; Immunoglobulin Gene Conversion; Center B-cells; Homologous Recombination; Dna-damage; Cycle; Chk1; Repair; Breaks; Radiation
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Zeitschrift Nucleic Acids Research
Quellenangaben Band: 42, Heft: 6, Seiten: 3666-3674 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Oxford
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)
Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
POF Topic(s) 30203 - Molecular Targets and Therapies
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501500-003
G-501400-001
PubMed ID 24423870
DOI 10.1093/nar/gkt1378
WOS ID WOS:000334758600025
Scopus ID 84898969703
Erfassungsdatum 2014-02-04
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