Details

Autor(en) / 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
• van der Maarel, Silvère M
• van Attikum, Haico

Titel

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

Ist Teil von

• The Journal of experimental medicine, 2020-11, Vol.217 (11)

Ort / Verlag

United States: Rockefeller University Press

Erscheinungsjahr

2020

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.