HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression
HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression
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DOI：
10.1016/j.celrep.2023.112284
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发表时间：
2023-03-20
期刊：
影响因子：
8.8
通讯作者：
Begum，Nasim A.
中科院分区：
文献类型：
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作者：
Refaat，Ahmed M.;Nakata，Mikiyo;Begum，Nasim A.
B细胞通过类别转换重组（CSR）产生功能上不同类别的抗体，这需要经典的非同源末端连接（C-NHEJ）来连接供体和受体转换（S）区处的DNA断裂。我们发现RNA结合蛋白HNRNPU通过53 BP 1-shieldin DNA修复复合物促进C-NHEJ介导的S-S连接。值得注意的是，HNRNPU与S区RNA/DNA G-四链体结合，有助于调节R-环和单链DNA（ssDNA）积累。HNRNPU是一种内在无序的蛋白质，以RNA依赖性方式与C-NHEJ和R-环复合物相互作用。引人注目的是，HNRNPU和C-NHEJ因子的募集对液-液相分离抑制剂高度敏感，表明DNA修复冷凝物形成。我们认为HNRNPU通过形成和稳定C-NHEJ核糖核蛋白复合物并防止R环过度积累来促进CSR，否则R环过度积累会导致持续的DNA断裂和异常的DNA修复，从而导致基因组不稳定。
B cells generate functionally different classes of antibodies through class-switch recombination (CSR), which requires classical non-homologous end joining (C-NHEJ) to join the DNA breaks at the donor and acceptor switch (S) regions. We show that the RNA-binding protein HNRNPU promotes C-NHEJ-mediated S-S joining through the 53BP1-shieldin DNA-repair complex. Notably, HNRNPU binds to the S region RNA/DNA G-quadruplexes, contributing to regulating R-loop and single-stranded DNA (ssDNA) accumulation. HNRNPU is an intrinsically disordered protein that interacts with both C-NHEJ and R-loop complexes in an RNA-dependent manner. Strikingly, recruitment of HNRNPU and the C-NHEJ factors is highly sensitive to liquid-liquid phase separation inhibitors, suggestive of DNA-repair condensate formation. We propose that HNRNPU facilitates CSR by forming and stabilizing the C-NHEJ ribonucleoprotein complex and preventing excessive R-loop accumulation, which otherwise would cause persistent DNA breaks and aberrant DNA repair, leading to genomic instability.