Exploring the zinc-binding proteins in the mutational hotspots of human cancer

Abstract

Mutations and zinc (Zn) ions are crucial in cancer biology. This study examines the tripartite relationship between mutations, zinc-binding proteins (ZBPs), and cancer. A total of 75 ZBPs were identified that may contribute to cancer after undergoing mutations. It was determined that positively charged amino acids such as histidine, arginine, and lysine, alongside negatively charged aspartic acid and glutamic acid, as well as the polar amino acid cysteine, can bind to Zn ions in cancer-related ZBPs. Most cancer-related ZBPs are intracellularly localized, found in the nucleoplasm, nuclear vesicles, and nucleoli, and primarily function as transferases or DNA-binding proteins. These cancer-related ZBPs are located on chromosomes 3, 11, and 19. A total of 46 cancer-related ZBPs exhibited interactions with one another, demonstrating complex inter- and intracellular co-regulation of molecular functions and protein-protein interactions. Mutations impact the Zn ion binding sites of many cancer-related ZBPs. Eleven cancer-related ZBPs (TRIM24, WT1, BCL6, MECOM, PATZ1, IKZF3, ZBTB16, ZNF521, BCL11B, TRIM33, and RAF1) were identified as oncogenic, tumor suppressor, and fusion proteins. The analysis of mutations in the Zn ion binding sites of the ZBPs revealed that mutations affect the proteins’ structure, function, and binding affinity, potentially leading to cancer. Investigating mutations in the Zn binding sites of these proteins will pave the way for cancer treatments by enhancing our understanding of their role in cancer spread and invasion.