BCL6 represses CHEK1 and suppresses DNA damage pathways in normal and malignant B-cells
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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.
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BCL6 represses a broad range of genes involved in the DNA damage response, cell cycle checkpoints, and differentiation.
“BCL6 represses a broad range of genes involved in the DNA damage response18, cell cycle checkpoints19, and differentiation20.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [18]
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A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo
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Self-citationSmall-molecule-induced polymerization triggers degradation of BCL6
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- Authors
- Ranuncolo, S. M., Polo, J. M., & Melnick, A.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Melnick, Ari
- Venue
- Blood Cells, Molecules, and Diseases
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 41
- Issue
- 1
- Pages
- 95-99
- ISSN
- 1079-9796 (ISSN-L)
- PMC
- PMC2723786
- OpenAlex
- W2085524373
- Cited by
- 116
- References
- 34
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 13 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 9 · 2017: 4 · 2016: 6 · 2015: 6 · 2014: 9 · 2013: 2 · 2012: 8
- FWCI
- 4.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood Cells Molecules and Diseases (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Leukemia and Lymphoma Society
- National Cancer Institute (R01CA104348)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- BCL6, Chk1, diffuse large B-cell lymphoma, DNA damage response, ATR kinase, transcriptional repression, germinal center B cells, p53, TP53, p21, genotoxic stress, B cell maturation
- MeSH terms
- Checkpoint Kinase 1, B-Lymphocytes, DNA Damage, Humans, Promoter Regions, Genetic, Protein Kinases, Lymphoma, Large B-Cell, Diffuse, Germinal Center, Cell Line, Tumor, Chromatin Immunoprecipitation, Proto-Oncogene Proteins c-bcl-6
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