Caught with One's Zinc Fingers in the Genome Integrity Cookie Jar

Abstract

Zinc finger (ZnF) domains are present in at least 5% of human proteins. First characterized as binding to DNA, ZnFs display extraordinary binding plasticity and can bind to RNA, lipids, proteins, and protein post-translational modifications (PTMs). The diverse binding properties of ZnFs have made their functional characterization challenging. While once confined to large and poorly characterized protein families, proteomic, cellular, and molecular studies have begun to shed light on their involvement as protectors of the genome. We focus here on the emergent roles of ZnF domain-containing proteins in promoting genome integrity, including their involvement in telomere maintenance and DNA repair. These findings have highlighted the need for further characterization of ZnF proteins, which can reveal the functions of this large gene class in normal cell function and human diseases, including those involving genome instability such as aging and cancer.

Keywords: DNA damage; DNA double-strand breaks; DNA repair; genome integrity; telomeres; zinc finger..

Figure 1 (Key Figure). Macromolecular binding specificities of zinc finger domains

(A) Zinc finger domains bind several types of substrates in addition to nucleic acids. (B) List of zinc finger domains and their binding substrates.

Figure 2. ZNF domains involved in the ZMYND8-mediated DDR pathway

Binding of PARP to DNA DSBs through its PARP ZNF domain promotes recruitment of KDM5A. The ZnF-containing PHD domain of KDM5A recognizes and promotes the demethylation of H3K4me3 near DSBs, allowing ZMYND8 to bind to acetylated chromatin and DNA through its PHD-BRD-PWWP and ZnF domains respectively. The ZnF MYND domain of ZMYND8 interacts with the PPPLΦ motif of NuRD subunit GATAD2A, recruiting the NuRD complex to damage sites to promote repression of active transcription and DNA repair of DSBs. ZMYND8 interacts with a complex containing ZNF532, ZNF592 and ZNF687, which also associate with damage sites and regulate this pathway.

Figure 3. ZNF proteins and telomere maintenance

Telomere length is determined by the balance between telomere erosion and telomere elongation processes. The ZNF-containing proteins TZAP, ZNF827 and ZSCAN4 play key roles in promoting telomere homeostasis under various physiological conditions (see text for details).