蛋白质中含有RNB结构域，在大多数生物种类中得以广泛存在，最初在大肠杆菌RNase II中被发现。许多RNB蛋白质具有3'-5'外切核糖核酸酶活性，但在进化过程中，有些蛋白质丢失了催化活性。通过数据库搜索，我们在人体中鉴定出了一个新的含有RNB结构域的蛋白质，命名为HELZ2。基因组和表达数据的分析以及进化信息的结合表明，人体HELZ2蛋白质是通过人科动物中的一个意外的非典型起始密码子产生的。这种不寻常的特性经过实验证实，人体蛋白质增加了247个残基。尽管在其催化中心中有关键残基的替代，但人体HELZ2被证明仍然是一个活性核酸酶。某些癌症患者细胞中的体细胞突变导致HELZ2 RN酶活性的丧失。HELZ2还含有两个RNA解旋酶结构域和数个锌指结构域，其表达受到干扰素处理的诱导。我们证明，HELZ2能够通过协调的ATP依赖的RNA解旋酶结构域介导的双链RNA位移和其3'-5'核酸酶酶活性来降解有结构的RNA。HELZ2的表达特征和生化特性支持其在对抗病毒和/或移动元件的响应中的作用。《作者(们) 2023. 版权所有，由牛津大学出版社代表核酸研究发表。》

Proteins containing a RNB domain, originally identified in Escherichia coli RNase II, are widely present throughout the tree of life. Many RNB proteins have 3'-5' exoribonucleolytic activity but some have lost catalytic activity during evolution. Database searches identified a new RNB domain-containing protein in human: HELZ2. Analysis of genomic and expression data combined with evolutionary information suggested that the human HELZ2 protein is produced from an unforeseen non-canonical initiation codon in Hominidae. This unusual property was confirmed experimentally, extending the human protein by 247 residues. Human HELZ2 was further shown to be an active ribonuclease despite the substitution of a key residue in its catalytic center. HELZ2 RNase activity is lost in cells from some cancer patients as a result of somatic mutations. HELZ2 harbors also two RNA helicase domains and several zinc fingers and its expression is induced by interferon treatment. We demonstrate that HELZ2 is able to degrade structured RNAs through the coordinated ATP-dependent displacement of duplex RNA mediated by its RNA helicase domains and its 3'-5' ribonucleolytic action. The expression characteristics and biochemical properties of HELZ2 support a role for this factor in response to viruses and/or mobile elements.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.