Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome
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- Angela Helfricht
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Peter E. Thijssen
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Magdalena B. Rother
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Rashmi G. Shah
- CHU de Québec Research Centre (site CHUL) and Laboratory for Skin Cancer Research and Axe Neuroscience, Université Laval, Québec, Canada 2
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- Likun Du
- Department of Biosciences and Nutrition, Karolinska Institute, Solna, Sweden 3
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- Sanami Takada
- Laboratory for Pediatric Immunology, Department of Pediatrics, Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands 4
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- Mélanie Rogier
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France 5
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- Jacques Moritz
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France 5
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- Hanna IJspeert
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands 9
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- Chantal Stoepker
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Monique M. van Ostaijen-ten Dam
- Laboratory for Pediatric Immunology, Department of Pediatrics, Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands 4
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- Vincent Heyer
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France 5
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- Martijn S. Luijsterburg
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Anton de Groot
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Rianca Jak
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Gwendolynn Grootaers
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Jun Wang
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Pooja Rao
- ServiceXS B.V., Leiden, Netherlands 10
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- Alfred C.O. Vertegaal
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands 11
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- Maarten J.D. van Tol
- Laboratory for Pediatric Immunology, Department of Pediatrics, Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands 4
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- Qiang Pan-Hammarström
- Department of Biosciences and Nutrition, Karolinska Institute, Solna, Sweden 3
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- Bernardo Reina-San-Martin
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France 5
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- Girish M. Shah
- CHU de Québec Research Centre (site CHUL) and Laboratory for Skin Cancer Research and Axe Neuroscience, Université Laval, Québec, Canada 2
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- Mirjam van der Burg
- Laboratory for Pediatric Immunology, Department of Pediatrics, Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands 4
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- Silvère M. van der Maarel
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
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- Haico van Attikum
- Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands 1
説明
<jats:p>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.</jats:p>
収録刊行物
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- Journal of Experimental Medicine
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Journal of Experimental Medicine 217 (11), 2020-08-31
Rockefeller University Press
