Structural and Functional Analysis of Gene and Protein Sequence Families

National Library Of Medicine

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Abstract

Nucleosomes comprise of 147 bp of DNA wrapped around a histone octamer and are central in coordinating various signaling pathways involved in epigenetic regulation. The molecular recognition of nucleosomes by chromatin factors frequently occurs through the interactions with the nucleosomal and linker DNA, histone tails, and histone globular domains as well as by recognizing their specific covalent modifications. Therefore, elucidating the molecular mechanism of interactions between histone/nucleosome and various chromatin factors is essential for our understanding of the principles of chromatin organization and regulation. Protein interaction networks allow for the large-scale measurements of protein-protein interactions (PPIs) in various cellular compartments of different species, but a comprehensive human protein interactome characterization remains a challenge. Previously, we performed a comprehensive mapping of human histone and nucleosome interactions by systematically analyzing the structural, chemical cross-linking, and high-throughput data. Now we are studying histone gene mutations in cancer. Histones are key epigenetic factors that regulate the accessibility and compaction of eukaryotic genomes, affecting DNA replication and repair, and gene expression. Recent studies have demonstrated that histone missense mutations can perturb normal histone function, promoting the development of phenotypically distinguishable cancers. However, most histone mutations observed in cancer patients remain enigmatic in their potential to promote cancer development. To assess the oncogenic potential of histone missense mutations, we have gathered whole-exome sequencing data for the tumors of about 12,000 patients. We found that histone mutations occurred in about 16% of cancer patients, although specific cancer types showed substantially higher rates. Using genomic, structural, and biophysical analyses, we found several predominant modes of action by which histone mutations may alter function. We report that cancer missense mutations affected histone acidic patch residues and protein binding interfaces in a cancer-specific manner and targeted interaction interfaces with specific DNA repair proteins. Consistent with this finding, we observed a high tumor mutational burden in patients with histone mutations affecting interactions with proteins involved in maintaining genome integrity. We identified potential cancer driver mutations in several histone genes, including mutations on histone H4 – a highly conserved histone without previously documented driver mutations.