53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination.
The mammalian protein 53BP1 is activated in many cell types in response to genotoxic stress, including DNA double-strand breaks (DSBs). We now examine potential functions for 53BP1 in the specific genomic alterations that occur in B lymphocytes. Although 53BP1 was dispensable for V(D)J recombination and somatic hypermutation (SHM), the processes by which immunoglobulin (Ig) variable region exons are assembled and mutated, it was required for Igh class-switch recombination (CSR), the recombination and deletion process by which Igh constant region genes are exchanged. When stimulated to undergo CSR, 53BP1-deficient cells exhibited no defect in C(H) germline transcription or AID expression, however these cells had a profound decrease in switch junctions. The current findings, in combination with the known 53BP1 functions and how it is activated, implicate the DNA damage response to DSBs in the joining phase of class-switch recombination.
Manis
John P
JP
Howard Hughes Medical Institute, The Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. manis@enders.tch.harvard.edu
Morales
Julio C
JC
Xia
Zhenfang
Z
Kutok
Jeffery L
JL
Alt
Frederick W
FW
Carpenter
Phillip B
PB
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D017578:Immunoglobulin Class Switching / Q000235:genetics* / Q000276:immunology; D007127:Immunoglobulin Constant Regions / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins
D002352:Carrier Proteins; C092537:Ifi202b protein, mouse; D007127:Immunoglobulin Constant Regions; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins