Krüppel相关盒锌指蛋白（KZFPs）通过调控转座子元件（TEs）的转录活性，作为高等脊椎动物基因组稳定性的防御机制。尽管先前的研究已经确定了ZFP809负责在小鼠中结合和抑制包含脯氨酰tRNA引物结合位点（PBS-Pro）的内源性反转录病毒（ERVs），但在人类中尚未鉴定出可比较的KZFPs。在这里，我们鉴定出ZNF506作为人类中结合PBS-Pro的蛋白质，通过招募异染色质修饰起到转录抑制剂的作用，来抵御利用PBS-Pro的逆转录病毒。尽管它们具有相似的功能，但ZNF506、ZFP809和其他物种的KZFPs之间的蛋白质相似性较低，表明它们在种群分化后独立进化以抵御PBS-Pro利用逆转录病毒的入侵。我们还探索了ZNF506与白血病之间的关联。我们的研究结果表明，ZNF506是一种具有结合PBS-Pro能力的独特人类KZFP，突显了KZFPs在防御逆转录病毒入侵方面的多样进化。此外，我们的研究还提供了关于ZNF506在白血病中潜在作用的见解，有助于扩展对KZFPs在疾病和基因组稳定性中关键功能的认识。© 2023作者。牛津大学出版社代表核酸研究。

Krüppel-associated box zinc finger proteins (KZFPs) function as a defense mechanism to maintain the genome stability of higher vertebrates by regulating the transcriptional activities of transposable elements (TEs). While previous studies have characterized ZFP809 as responsible for binding and repressing ERVs containing a proline tRNA primer-binding site (PBS-Pro) in mice, comparable KZFPs have not been identified in humans yet. Here, we identified ZNF506 as a PBS-Pro-binding protein in humans, which functions as a transcriptional repressor of PBS-Pro-utilizing retroviruses by recruiting heterochromatic modifications. Although they have similar functions, the low protein similarities between ZNF506, ZFP809 and KZFPs of other species suggest their independent evolution against the invasion of PBS-Pro-utilizing retroviruses into their respective ancestor genomes after species divergence. We also explored the link between ZNF506 and leukemia. Our findings suggest that ZNF506 is a unique human KZFP that can bind to PBS-Pro, highlighting the diverse evolution of KZFPs in defending against retroviral invasions. Additionally, our study provides insights into the potential role of ZNF506 in leukemia, contributing to the expanding knowledge of KZFPs' crucial function in disease and genome stability.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.