MSc Student, Aristizabal Lab Characterizing the effects of human cancer-associated histone H2AZ mutations using S. cerevisiae Nucleosomes, the building blocks of chromatin, are composed of 146 base pairs of DNA wrapped around an octamer of histone proteins (typically two copies of H2A, H2B, H3, and H4). Chromatin, the packing structure by which DNA is condensed into chromosomes, is dynamic and can be altered in several ways, including: (1) the sliding, eviction, and deposition of nucleosomes, (2) the addition of posttranslational modifications (PTMs) to histone proteins and (3) the incorporation of histone variants in place of canonical counterparts. A wide range of mutations on histone-encoding genes have been identified among publicly available whole-exome sequencing data from human cancer patients. Some of these mutations have been demonstrated to disrupt the histone octamer, alter higher order chromatin structure, and affect histone tail dynamics, DNA accessibility and transcription factor binding. Although most of these mutations remain to be studied, some, termed “oncohistones,” have been shown to drive cancer development and are correlated with poor disease prognosis. My project seeks to advance our understanding of the effect(s) of these cancer-associated missense mutations to the histone H2A variant, H2A.Z, using budding yeast (Saccharomyces cerevisiae) as a model system. H2A.Z is implicated in a wide range of molecular processes, including transcriptional regulation, DNA replication, cell cycle progression, and DNA damage repair. It is also highly conserved from yeast to humans. Focusing on cancer-associated mutations that map to identical residues between yeast and humans, we have generated a library of 21 mutations which will be screened for effects on cellular growth, chromatin dynamics, and gene expression. This work will improve our understanding of the various mechanisms by which cancer-associated mutations affect genome function, providing some clues as to how they may contribute to cancer development and progression.
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