The Journal of experimental medicine · 2020
Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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, van der Maarel Silvère M, van Attikum Haico
Аннотация
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.