Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR
Abstract
Antibody specificity and diversity is generated in B cells during germinal center maturation through clonal expansion while they undergo class-switch recombination and somatic hypermutation. Here we demonstrate that the transcriptional repressor Bcl-6 mediates this phenotype by directly repressing ATR in centroblasts and lymphoma cells. ATR is critical in replication and DNA damage-sensing checkpoints. Bcl-6 allowed B cells to evade ATR-mediated checkpoints and attenuated the response of the B cells to exogenous DNA damage. Repression of ATR was necessary and sufficient for those Bcl-6 activities. CD40 signaling 'rescued' B cells from those effects by disrupting the Bcl-6 transcription-repression complex on the promoter of the gene encoding ATR. Our data demonstrate a transcriptional regulatory loop whereby Bcl-6 mediates the centroblast phenotype through transient silencing of ATR.
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BCL-6 leads to reduced CHK1 phosphorylation through ATR inhibition, which subsequently facilitates DNA replication.
“For instance, BCL-6, an oncogene involved in B lymphoma, leads to reduced CHK1 phosphorylation through ATR inhibition, which subsequently facilitates DNA replication [32].”
From The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia (2017) · cites this paper as [32]
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References 51 · Cited by 278
- Authors
- Ranuncolo, S. M., Polo, J. M., Dierov, J., Singer, M., Kuo, T., Greally, J., Green, R., Carroll, M., & Melnick, A.
- Affiliations
- Albert Einstein College of Medicine (US)
- University of Pennsylvania (US)
- University of California, Berkeley (US)
- Corresponding author
- Carroll, Martin
- Melnick, Ari
- Venue
- Nature Immunology
- Published
- 2007-06-10
- Volume
- 8
- Issue
- 7
- Pages
- 705-714
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2006885289
- Cited by
- 278
- References
- 51
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 14 · 2023: 16 · 2022: 11 · 2021: 9 · 2020: 9 · 2019: 12 · 2018: 16 · 2017: 10 · 2016: 14 · 2015: 14 · 2014: 18 · 2013: 15 · 2012: 22
- FWCI
- 9.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA104348, R01CA100885)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- BCL6, ATR, germinal center B cells, centroblasts, lymphomagenesis, transcriptional repression, DNA damage checkpoint, CD40 signaling, somatic hypermutation, class switch recombination, B cell clonal expansion
- MeSH terms
- Cells, Cultured, DNA Damage, DNA-Binding Proteins, Humans, Down-Regulation, Immunophenotyping, B-Lymphocyte Subsets, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Germinal Center, Gene Silencing, Cell Line, Tumor, Proto-Oncogene Proteins c-bcl-6, Ataxia Telangiectasia Mutated Proteins
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