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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        Publication type
        Article: Journal article
    
 
    
        Document type
        Scientific Article
    
 
    
        Thesis type
        
    
 
    
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        Keywords
        Induced Cytidine Deaminase; Immunoglobulin Gene Conversion; Center B-cells; Homologous Recombination; Dna-damage; Cycle; Chk1; Repair; Breaks; Radiation
    
 
    
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        Language
        english
    
 
    
        Publication Year
        2014
    
 
    
        Prepublished in Year
        
    
 
    
        HGF-reported in Year
        2014
    
 
    
    
        ISSN (print) / ISBN
        0305-1048
    
 
    
        e-ISSN
        1362-4962
    
 
    
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	    Volume: 42,  
	    Issue: 6,  
	    Pages: 3666-3674 
	    Article Number: ,  
	    Supplement: ,  
	
    
 
    
        
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            Publisher
            Oxford University Press
        
 
        
            Publishing Place
            Oxford
        
 
	
        
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        Reviewing status
        Peer reviewed
    
 
     
    
        POF-Topic(s)
        30203 - Molecular Targets and Therapies
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
    
 
    
        Research field(s)
        Immune Response and Infection
    
 
    
        PSP Element(s)
        G-501500-003
G-501400-001
    
 
    
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        Erfassungsdatum
        2014-02-04