BCL6 represses CHEK1 and suppresses DNA damage pathways in normal and malignant B-cells.
BCL6 is a transcriptional repressor protein that is expressed in a developmentally regulated fashion during B-cell maturation. Specifically, BCL6 is required for formation of germinal centers in response to T-cell dependent antigen activation. Germinal center B-cells feature the ability to tolerate rapid proliferation and simultaneous genetic recombination. Genetic lesions that cause constitutive expression of BCL6 are commonly associated with diffuse large B-cell lymphomas (DLBCL). Recent studies show that BCL6 contributes to the germinal center phenotype by directly repressing genes involved in sensing or responding to DNA damage including ATR, TP53 and CDKN1A. The CHEK1 protein is activated through phosphorylation by the ATR kinase domain in response to DNA damage. Activated CHEK1 can phosphorylate and modulate the activity a number of proteins including p53, providing a link between ATR sensing of DNA damage and p53 checkpoint activity. Herein we show that BCL6 can directly bind to a DNA consensus element in the CHEK1 promoter and repress its expression in normal and malignant B-cells. DLBCL cells can be killed by a specific BCL6 peptide inhibitor (BPI) that interferes with corepressor binding to the BCL6 BTB domain. BPI could reactivate CHEK1 in DLBCL cells, suggesting that its induction might contribute to BPI anti-lymphoma effects. Therefore, BCL6 can suppress multiple genes involved in a common pathway sensing, transducing and responding to genotoxic stress.
Ranuncolo
Stella M
SM
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York 10128, USA.
Polo
Jose M
JM
Melnick
Ari
A
D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D047369:Chromatin Immunoprecipitation; D004249:DNA Damage; D018858:Germinal Center / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*
D051560:Proto-Oncogene Proteins c-bcl-6; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1