Genotoxic stress regulates expression of the proto-oncogene Bcl6 in germinal center B cells.
Antigen-specific B cells are selected in germinal centers, the structure in which these cells proliferate while accomplishing genome-remodeling processes such as class-switch recombination and somatic hypermutation. These events are associated with considerable genotoxic stress, which cells tolerate through suppression of DNA-damage responses by Bcl-6, a transcription factor required for the formation of germinal centers. Here we show that the expression of Bcl-6 is regulated by DNA damage through a signaling pathway that promotes Bcl-6 degradation. After DNA damage accumulated, the kinase ATM promoted Bcl-6 phosphorylation, leading to its interaction with the isomerase Pin1 and its degradation by the ubiquitin-proteasome system. Because Bcl-6 is required for the maintenance of germinal centers, our findings suggest that the extent of genotoxic stress controls the fate of germinal center B cells by means of Bcl-6.
Phan
Ryan T
RT
Institute for Cancer Genetics, the Department of Pathology and Genetics & Development, Columbia University, New York, New York 10032, USA.
Saito
Masumichi
M
Kitagawa
Yukiko
Y
Means
Anthony R
AR
Dalla-Favera
Riccardo
R
D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000502:physiology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000378:metabolism*; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D011519:Proto-Oncogenes; D025521:Tumor Suppressor Proteins / Q000502:physiology