Laffleur Brice, Basu Uttiya, Lim Junghyun
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
J Mol Biol. 2017 Oct 27;429(21):3230-3241. doi: 10.1016/j.jmb.2016.12.021. Epub 2017 Jan 7.
The eukaryotic RNA exosome is a well-conserved protein complex with ribonuclease activity implicated in RNA metabolism. Various families of non-coding RNAs have been identified as substrates of the complex, underscoring its role as a non-coding RNA processing/degradation unit. However, the role of RNA exosome and its RNA processing activity on DNA mutagenesis/alteration events have not been investigated until recently. B lymphocytes use two DNA alteration mechanisms, class switch recombination (CSR) and somatic hypermutation (SHM), to re-engineer their antibody gene expressing loci until a tailored antibody gene for a specific antigen is satisfactorily generated. CSR and SHM require the essential activity of the DNA activation-induced cytidine deaminase (AID). Causing collateral damage to the B-cell genome during CSR and SHM, AID induces unwanted (and sometimes oncogenic) mutations at numerous non-immunoglobulin gene sequences. Recent studies have revealed that AID's DNA mutator activity is regulated by the RNA exosome complex, thus providing an example of a mechanism that relates DNA mutagenesis to RNA processing. Here, we review the emergent functions of RNA exosome during CSR, SHM, and other chromosomal alterations in B cells, and discuss implications relevant to mechanisms that maintain B-cell genomic integrity.
真核生物RNA外切体是一种具有核糖核酸酶活性的高度保守的蛋白质复合物，参与RNA代谢。多种非编码RNA家族已被确定为该复合物的底物，这突出了其作为非编码RNA加工/降解单元的作用。然而，直到最近，RNA外切体及其RNA加工活性在DNA诱变/改变事件中的作用仍未得到研究。B淋巴细胞利用两种DNA改变机制，即类别转换重组（CSR）和体细胞高频突变（SHM），来重新构建其抗体基因表达位点，直到产生针对特定抗原的定制抗体基因。CSR和SHM需要DNA激活诱导的胞苷脱氨酶（AID）的基本活性。在CSR和SHM过程中，AID会对B细胞基因组造成附带损害，在许多非免疫球蛋白基因序列上诱导产生不必要的（有时是致癌的）突变。最近的研究表明，AID的DNA诱变活性受RNA外切体复合物调控，从而提供了一个将DNA诱变与RNA加工联系起来的机制实例。在此，我们综述了RNA外切体在B细胞CSR、SHM及其他染色体改变过程中的新功能，并讨论了与维持B细胞基因组完整性机制相关的意义。
