Keeping it centered: decoding the activities that regulate yeast histone H3 variant Cse4 and confine it to centromeres

. Fifteen years later, the discovery that the yeast histone H3 variant Cse4 is the conserved counterpart of human CENP-A established both proteins as the defining epigenetic marks of centromeres. Subsequent genetic screens, biochemical and molecular biology studies have elucidated how Cse4 is specifically targeted to and stably maintained at centromeres. The mislocalization of Cse4 beyond centromeres disrupts transcriptional programs and drives chromosomal instability and aneuploidy. This review traces Cse4 research from its early breakthroughs to current insights into its regulatory pathways. Although derived from yeast, these mechanistic advances provide a conceptual framework for understanding analogous, and likely conserved, processes in humans, where CENP-A biology remains less well defined but is increasingly being implicated in cancer and therapy resistance when perturbed.