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Helfricht, Angela; Thijssen, Peter E.; Rother, Magdalena B.; Shah, Rashmi G.; Du, Likun; Takada, Sanami; Rogier, Mélanie; Moritz, Jacques; IJspeert, Hanna; Stoepker, Chantal; van Ostaijen-ten Dam, Monique M.; Heyer, Vincent; Luijsterburg, Martijn S.; de Groot, Anton; Jak, Rianca; Grootaers, Gwendolynn; Wang, Jun; Rao, Pooja; Vertegaal, Alfred C.O.; van Tol, Maarten J.D.; Pan-Hammarström, Qiang; Reina-San-Martin, Bernardo; Shah, Girish M.; van der Burg, Mirjam; [...]

Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

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  • Medientyp: E-Artikel
  • Titel: Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome
  • Beteiligte: Helfricht, Angela; Thijssen, Peter E.; Rother, Magdalena B.; Shah, Rashmi G.; Du, Likun; Takada, Sanami; Rogier, Mélanie; Moritz, Jacques; IJspeert, Hanna; Stoepker, Chantal; van Ostaijen-ten Dam, Monique M.; Heyer, Vincent; Luijsterburg, Martijn S.; de Groot, Anton; Jak, Rianca; Grootaers, Gwendolynn; Wang, Jun; Rao, Pooja; Vertegaal, Alfred C.O.; van Tol, Maarten J.D.; Pan-Hammarström, Qiang; Reina-San-Martin, Bernardo; Shah, Girish M.; van der Burg, Mirjam; [...]
  • Erschienen: Rockefeller University Press, 2020
  • Erschienen in: Journal of Experimental Medicine
  • Sprache: Englisch
  • DOI: 10.1084/jem.20191688
  • ISSN: 0022-1007; 1540-9538
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <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>
  • Zugangsstatus: Freier Zugang