Abstract
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.
Highlights
Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome (OMIM 242860; 614069) is a rare autosomal recessive disorder characterized by a triad of phenotypes (Hagleitner et al, 2008; Weemaes et al, 2013)
We first examined the combinatorial diversity of VDJ usage and composition of the junctional region during V(D)J recombination by sequencing Ig heavy chain gene rearrangements in B cells derived from peripheral blood mononuclear cells (PBMCs) of three ICF2 patients
We found that class-switch recombination (CSR) junctions in B cells from ICF2 patients show an altered repair pattern with a decrease in direct endjoining and an increased usage of long microhomologies, suggesting a shift from the use of c-nonhomologous end-joining (NHEJ) to the use of alternative NHEJ (a-NHEJ) similar to that observed in B cells from ligase 4 (LIG4)- and Artemisdeficient patients (Table 1, Data S1, Data S2, and Data S3)
Summary
Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome (OMIM 242860; 614069) is a rare autosomal recessive disorder characterized by a triad of phenotypes (Hagleitner et al, 2008; Weemaes et al, 2013). ICF syndrome is genetically heterogeneous and can be subdivided into five different groups (ICF1-4 and ICFX) based on the genetic defect underlying the phenotype (Thijssen et al, 2015; Weemaes et al, 2013). Mutations in the cell division cycle–associated protein 7 (CDCA7, ICF3) or helicase, lymphoid-specific (HELLS, ICF4) were reported in patients (∼20% of the total patient population), leaving only a few cases genetically unaccounted for (ICFX; Thijssen et al, 2015). The genetic defects underlying ICF syndrome have been mostly elucidated, it remains largely unclear how these defects lead
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