2020-11-02
Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome
Publication
Publication
The Journal of experimental medicine , Volume 217 - Issue 11
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.
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| doi.org/10.1084/jem.20191688, hdl.handle.net/1765/130098 | |
| The Journal of experimental medicine | |
| Organisation | Department of Immunology |
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Helfricht, A. (Angela), Thijssen, P., Rother, M.B. (Magdalena B.), Shah, R.G. (Rashmi G.), Du, L., Takada, S. (Sanami), … van Attikum, H. (2020). Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome. The Journal of experimental medicine, 217(11). doi:10.1084/jem.20191688 |
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