Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR

Stella Maris Ranuncolo; Jose M. Polo; Jamil Dierov; Michael Singer; Tracy Kuo; John Greally; Roland Green; Martin Carroll; Ari Melnick

doi:10.1038/ni1478

Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR

Stella Maris Ranuncolo, Jose M. Polo, Jamil Dierov, Michael Singer, Tracy Kuo, John Greally, Roland Green, Martin Carroll, Ari Melnick

Research output: Contribution to journal › Article › peer-review

224 Scopus citations

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.

Original language	English (US)
Pages (from-to)	705-714
Number of pages	10
Journal	Nature Immunology
Volume	8
Issue number	7
DOIs	https://doi.org/10.1038/ni1478
State	Published - Jul 2007
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1038/ni1478

Cite this

@article{85ee9564f847416fa562395a54568c8b,

title = "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.",

author = "Ranuncolo, {Stella Maris} and Polo, {Jose M.} and Jamil Dierov and Michael Singer and Tracy Kuo and John Greally and Roland Green and Martin Carroll and Ari Melnick",

note = "Funding Information: We thank S. Schreiber and K. Cimprich for FLAG-ATR constructs, and A. Follenzi for assistance in establishing high-efficiency lentiviral transduction of primary B cells. Supported by the Cancer Research Institute (S.M.R.), the National Cancer Center (J.M.P.), the National Cancer Institute (R01 CA104348 to A.M. and R01 CA100885 to M.C.), the Leukemia and Lymphoma Society (A.M. and M.C.), the Chemotherapy Foundation (A.M.), the Samuel Waxman Cancer Research Foundation (A.M.) and the G&P Foundation (A.M.).",

year = "2007",

month = jul,

doi = "10.1038/ni1478",

language = "English (US)",

volume = "8",

pages = "705--714",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "7",

}

TY - JOUR

T1 - Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR

AU - Ranuncolo, Stella Maris

AU - Polo, Jose M.

AU - Dierov, Jamil

AU - Singer, Michael

AU - Kuo, Tracy

AU - Greally, John

AU - Green, Roland

AU - Carroll, Martin

AU - Melnick, Ari

N1 - Funding Information: We thank S. Schreiber and K. Cimprich for FLAG-ATR constructs, and A. Follenzi for assistance in establishing high-efficiency lentiviral transduction of primary B cells. Supported by the Cancer Research Institute (S.M.R.), the National Cancer Center (J.M.P.), the National Cancer Institute (R01 CA104348 to A.M. and R01 CA100885 to M.C.), the Leukemia and Lymphoma Society (A.M. and M.C.), the Chemotherapy Foundation (A.M.), the Samuel Waxman Cancer Research Foundation (A.M.) and the G&P Foundation (A.M.).

PY - 2007/7

Y1 - 2007/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34250762588&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250762588&partnerID=8YFLogxK

U2 - 10.1038/ni1478

DO - 10.1038/ni1478

M3 - Article

C2 - 17558410

AN - SCOPUS:34250762588

SN - 1529-2908

VL - 8

SP - 705

EP - 714

JO - Nature Immunology

JF - Nature Immunology

IS - 7

ER -

Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this