TopBP1 deficiency impairs V(D)J recombination during lymphocyte development

• Published in: The EMBO journal Vol. 33; no. 3; pp. 217 - 228
• Main Authors: Kim, Jieun, Kyu Lee, Sung, Jeon, Yoon, Kim, Yehyun, Lee, Changjin, Ho Jeon, Sung, Shim, Jaegal, Kim, In-Hoo, Hong, Seokmann, Kim, Nayoung, Lee, Ho, Seong, Rho Hyun
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 03.02.2014; Nature Publishing Group UK
• Subjects: Animals; Carrier Proteins - genetics; Carrier Proteins - immunology; Carrier Proteins - metabolism; Chromatin Immunoprecipitation; Defects; Deoxyribonucleic acid; DNA; DNA - genetics; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; EMBO19; Gene Expression; Histones - genetics; Histones - metabolism; lymphocyte development; Lymphocytes; Lymphocytes - immunology; Lymphocytes - physiology; Mice; Mice, Knockout; Natural Killer T-Cells - immunology; Natural Killer T-Cells - physiology; Precursor Cells, B-Lymphoid - immunology; Precursor Cells, B-Lymphoid - physiology; Sequence Deletion; Specific Pathogen-Free Organisms; T cell receptors; TopBP1; Transgenes; V(D)J Recombination - genetics; V(D)J Recombination - immunology; VDJ recombination; VDJ recombination; TopBP1; lymphocyte development
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/embj.201284316

TopBP1 was initially identified as a topoisomerase II‐β‐binding protein and it plays roles in DNA replication and repair. We found that TopBP1 is expressed at high levels in lymphoid tissues and is essential for early lymphocyte development. Specific abrogation of TopBP1 expression resulted in transitional blocks during early lymphocyte development. These defects were, in major part, due to aberrant V(D)J rearrangements in pro‐B cells, double‐negative and double‐positive thymocytes. We also show that TopBP1 was located at sites of V(D)J rearrangement. In TopBP1‐deficient cells, γ‐H2AX foci were found to be increased. In addition, greater amount of γ‐H2AX product was precipitated from the regions where TopBP1 was localized than from controls, indicating that TopBP1 deficiency results in inefficient DNA double‐strand break repair. The developmental defects were rescued by introducing functional TCR αβ transgenes. Our data demonstrate a novel role for TopBP1 as a crucial factor in V(D)J rearrangement during the development of B, T and i NKT cells. Synopsis TopBP1 is needed for V(D)J rearrangement during development of B, T and iNKT cells. TopBP1 is highly expressed during lymphocyte development. Deletion of TopBP1 leads to immune deficiency and the lack of mature B and T cells. Ablation of TopBP1 results in increased double strand breaks due to inefficient V(D)J recombination. These defects are rescued by expressing pre‐rearranged TCR transgenes, supporting that TopBP1 plays a role during V(D)J recombination. . Graphical Abstract TopBP1 is needed for V(D)J rearrangement during development of B, T and iNKT cells.