53BP1 Contributes toIghLocus Chromatin Topology during Class Switch Recombination.
In B lymphocytes, Ig class switch recombination (CSR) is induced by activation-induced cytidine deaminase, which initiates a cascade of events leading to DNA double-strand break formation in switch (S) regions. Resolution of DNA double-strand breaks proceeds through formation of S-S synaptic complexes. S-S synapsis is mediated by a chromatin loop that spans the C region domain of theIghlocus. S-S junctions are joined via a nonhomologous end joining DNA repair process. CSR occurs via an intrachromosomal looping out and deletion mechanism that is 53BP1 dependent. However, the mechanism by which 53BP1 facilitates deletional CSR and inhibits inversional switching events remains unknown. We report a novel architectural role for 53BP1 inIghchromatin looping in mouse B cells. Long-range interactions between the Eμ and 3'Eα enhancers are significantly diminished in the absence of 53BP1. In contrast, germline transcript promoter:3'Eα looping interactions are unaffected by 53BP1 deficiency. Furthermore, 53BP1 chromatin occupancy at sites in theIghlocus is B cell specific, is correlated with histone H4 lysine 20 marks, and is subject to chromatin spreading. Thus, 53BP1 is required for three-dimensional organization of theIghlocus and provides a plausible explanation for the link with 53BP1 enforcement of deletional CSR.
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344; and.
Scott
S
Feldman
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344; and.
Robert
R
Wuerffel
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344; and.
Ikbel
I
Achour
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344; and.
Lili
0000-0002-8185-431X
L
Wang
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX 77030.
Phillip B
PB
Carpenter
Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612-7344; and star1@uic.edu.
Amy L
AL
Kenter
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000276:immunology / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004742:Enhancer Elements, Genetic / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D011995:Recombination, Genetic; D019749:Sulfur-Sulfur Bond Isomerases / Q000235:genetics / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; D006657:Histones; D007143:Immunoglobulin Heavy Chains; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D007073:Immunoglobulin E; D003564:Cytidine Deaminase; D019749:Sulfur-Sulfur Bond Isomerases