Different modes of engagement with the nucleosome acidic patch yield distinct functional outcomes

The nucleosome acidic patch is a hub of coordinated engagement by proteins that regulate genomic function. Here we report that <i>S. cerevisiae</i> Dot5 contains an arginine-rich HMGN-like motif that mediates nucleosome acidic patch binding and is required for the cell growth, DNA repair and heterochromatin defects exhibited when the protein is overexpressed. The heterologous expression of camelid single chain antibodies to the nucleosome acidic patch confers a similar range of phenotypes, with the most severe observed when an 'arginine-anchor' mode of binding analogous to many endogenous factors is employed. This highlights a delicate balance between nucleosome acidic patch interactors critical for normal cellular functions and dysregulated in disease.