Zheng Simin, Vuong Bao Q, Vaidyanathan Bharat, Lin Jia-Yu, Huang Feng-Ting, Chaudhuri Jayanta
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Biology, City College of New York, New York, NY 10031, USA.
Cell. 2015 May 7;161(4):762-73. doi: 10.1016/j.cell.2015.03.020.
Transcription through immunoglobulin switch (S) regions is essential for class switch recombination (CSR), but no molecular function of the transcripts has been described. Likewise, recruitment of activation-induced cytidine deaminase (AID) to S regions is critical for CSR; however, the underlying mechanism has not been fully elucidated. Here, we demonstrate that intronic switch RNA acts in trans to target AID to S region DNA. AID binds directly to switch RNA through G-quadruplexes formed by the RNA molecules. Disruption of this interaction by mutation of a key residue in the putative RNA-binding domain of AID impairs recruitment of AID to S region DNA, thereby abolishing CSR. Additionally, inhibition of RNA lariat processing leads to loss of AID localization to S regions and compromises CSR; both defects can be rescued by exogenous expression of switch transcripts in a sequence-specific manner. These studies uncover an RNA-mediated mechanism of targeting AID to DNA.
通过免疫球蛋白转换（S）区域进行转录对于类别转换重组（CSR）至关重要，但这些转录本的分子功能尚未得到描述。同样，激活诱导的胞苷脱氨酶（AID）募集到S区域对于CSR至关重要；然而，其潜在机制尚未完全阐明。在这里，我们证明内含子转换RNA以反式作用将AID靶向S区域DNA。AID通过RNA分子形成的G-四链体直接与转换RNA结合。通过AID假定的RNA结合结构域中一个关键残基的突变破坏这种相互作用，会损害AID募集到S区域DNA，从而消除CSR。此外，抑制RNA套索加工会导致AID在S区域的定位丧失并损害CSR；这两个缺陷都可以通过以序列特异性方式外源表达转换转录本来挽救。这些研究揭示了一种将AID靶向DNA的RNA介导机制。
