H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation.
Changes in chromatin structure induced by posttranslational modifications of histones are important regulators of genomic function. Phosphorylation of histone H2AX promotes DNA repair and helps maintain genomic stability. Although B cells lacking H2AX show impaired class switch recombination (CSR), the precise role of H2AX in CSR and somatic hypermutation (SHM) has not been defined. We show that H2AX is not required for SHM, suggesting that the processing of DNA lesions leading to SHM is fundamentally different from CSR. Impaired CSR in H2AX-/- B cells is not due to alterations in switch region transcription, accessibility, or aberrant joining. In the absence of H2AX, short-range intra-switch region recombination proceeds normally while long-range inter-switch region recombination is impaired. Our results suggest a role for H2AX in regulating the higher order chromatin remodeling that facilitates switch region synapsis.
Reina-San-Martin
Bernardo
B
Laboratory of Molecular Immunology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
Difilippantonio
Simone
S
Hanitsch
Leif
L
Masilamani
Revati F
RF
Nussenzweig
Andre
A
Nussenzweig
Michel C
MC
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D002843:Chromatin / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D007134:Immunoglobulin Switch Region / Q000235:genetics*; D007136:Immunoglobulins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D011995:Recombination, Genetic; D016415:Sequence Alignment; D027041:Somatic Hypermutation, Immunoglobulin
D002843:Chromatin; D006657:Histones; D007136:Immunoglobulins; C475961:gamma-H2AX protein, mouse