Unraveling the role of ZNF506 as a human PBS-pro-targeting protein for ERVP repression

Abstract

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.

Diversity and functional specialization of H3K9‐specific histone methyltransferases

“…For example, in mice, SetDB1 binds to them via KAP1–ZFP809, [ 142 ] and in humans, through interaction with KAP1–ZNF506. [ 143 ] KAP1 plays a role of a universal corepressor implementing SetDB1's recruitment to the sites that contain sequence motifs recognizable by various ZFP/ZNF proteins. KAP1 is a SUMO E3 ligase, and its autoSUMOylation is necessary for the guiding of SetDB1 to the sites.…”