ZNF224 Protein: Multifaceted Functions Based on Its Molecular Partners

Abstract

The transcription factor ZNF224 is a Kruppel-like zinc finger protein that consists of 707 amino acids and contains 19 tandemly repeated C2H2 zinc finger domains that mediate DNA binding and protein–protein interactions. ZNF224 was originally identified as a transcriptional repressor of genes involved in energy metabolism, and it was demonstrated that ZNF224-mediated transcriptional repression needs the interaction of its KRAB repressor domain with the co-repressor KAP1 and its zinc finger domains 1–3 with the arginine methyltransferase PRMT5. Furthermore, the protein ZNF255 was identified as an alternative isoform of ZNF224 that possesses different domain compositions mediating distinctive functional interactions. Subsequent studies showed that ZNF224 is a multifunctional protein able to exert different transcriptional activities depending on the cell context and the variety of its molecular partners. Indeed, it has been shown that ZNF224 can act as a repressor, an activator and a cofactor for other DNA-binding transcription factors in different human cancers. Here, we provide a brief overview of the current knowledge on the multifaceted interactions of ZNF224 and the resulting different roles of this protein in various cellular contexts.

The KRAB Domain of ZNF10 Guides the Identification of Specific Amino Acids That Transform the Ancestral KRAB-A-Related Domain Present in Human PRDM9 into a Canonical Modern KRAB-A Domain

“…KZNF proteins, often in concert with TRIM28, have been shown to participate in many biological processes, including cell proliferation, differentiation, development, imprinting, metabolism and pathophysiology [16,17]. With respect to cancer, KZNF proteins, as well as TRIM28 and SETDB1, have been shown to exert pleiotropic roles as oncogenes or tumor suppressors in different tumor types [20][21][22]. The ongoing evolutionary contention between host and retroviruses is considered a major source for expansion and emergence of new members of KZFN genes in species of different phylogenetic branches [23,24].…”

Comprehensive analysis of transcriptome characteristics and identification of TLK2 as a potential biomarker in dermatofibrosarcoma protuberans

“…As a member of the zinc finger protein family, ZNF286A is predicted to regulate the activity of DNA-binding transcription factors. Although other members of this family, such as ZNF224 (Cesaro et al, 2021) and ZNF217 (Li et al, 2021), play important roles in cancer development, the role of ZNF286A has not been studied in any disease. FAM20C is a Frontiers in Genetics frontiersin.org secreted protein with atypical kinase activity, which plays important roles in biomineralization, cell migration, and wound healing (Xu et al, 2021).…”

Zinc Finger Proteins in the War on Gastric Cancer: Molecular Mechanism and Clinical Potential

“…The conserved repeat is cysteine (Cys)-n2-4-Cys-N12-14-histidine (His)-N3-His; more specifically, two Cys sulfuryl groups and two His imidazolyl groups in this repetition domain are coordinated with Zn 2+ and stabilized via hydrophobic interaction [28]. Furthermore, ZFPs encompass other functional domains, such as Krüppel-associated box (KRAB), sre-ZBPbu, CTfin51, AW1 and Number 18 cDNA (SCAN), as well as the broad complex, tramtrack and bric-abrac/poxvirus and zinc finger (BTB/POZ) domains [29]. These functional domains may control DNA binding, subcellular localization and gene expression via regulating selective binding proteins [30][31][32].…”