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.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Frankenberger S,Davari K,Fischer-Burkart S,Böttcher K,Tomi NS,Zimber-Strobl U,Jungnickel Bdoi
10.1093/nar/gkt1378subject
Has Abstractpub_date
2014-04-01 00:00:00pages
3666-74issue
6eissn
0305-1048issn
1362-4962pii
gkt1378journal_volume
42pub_type
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