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Checkpoint kinase 1 negatively regulates somatic hypermutation.
Nucleic Acids Res. 42, 3666-3674 (2014)
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
ISSN (print) / ISBN
0305-1048
e-ISSN
1362-4962
Zeitschrift
Nucleic Acids Research
Quellenangaben
Band: 42,
Heft: 6,
Seiten: 3666-3674
Verlag
Oxford University Press
Verlagsort
Oxford
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed