Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome
| Autor: | Peter E. Thijssen, Qiang Pan-Hammarström, Mélanie Rogier, Girish M. Shah, Gwendolynn Grootaers, Mirjam van der Burg, Anton J.L. de Groot, Angela Helfricht, Rianca Jak, Alfred C.O. Vertegaal, Monique M. van Ostaijen-ten Dam, Jun Wang, Vincent Heyer, Magdalena B. Rother, Likun Du, Hanna IJspeert, Jacques Moritz, Maarten J. D. van Tol, Haico van Attikum, Bernardo Reina-San-Martin, Pooja Rao, Sanami Takada, Rashmi G. Shah, Martijn S. Luijsterburg, Silvère M. van der Maarel, Chantal Stoepker |
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| Přispěvatelé: | Immunology |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine DNA End-Joining Repair Primary Immunodeficiency Diseases Immunology Poly (ADP-Ribose) Polymerase-1 LIG4 Biology Transfection medicine.disease_cause Article Mice 03 medical and health sciences 0302 clinical medicine PARP1 medicine Immunodeficiency Animals Humans Immunology and Allergy B-Lymphocytes Mutation PARG DNA Breaks Genome Stability social sciences DNA repair protein XRCC4 Immunoglobulin Class Switching Isotype humanities Immunoglobulin Switch Region 3. Good health Cell biology Repressor Proteins Non-homologous end joining HEK293 Cells 030104 developmental biology Immunoglobulin class switching Face human activities Human Disease Genetics 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Journal of Experimental Medicine, 217(11). ROCKEFELLER UNIV PRESS The Journal of experimental medicine, 217(11) The Journal of Experimental Medicine |
| Popis: | Mutations in ZBTB24 cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. Helfricht et al. demonstrate that the loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination, proving a molecular basis for the immunodeficiency in ICF patients. The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome. Graphical Abstract |
| Databáze: | OpenAIRE |
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