The ATAD2/ANCCA homolog Yta7 cooperates with Scm3 to deposit Cse4 at the centromere in yeast.

The AAA ATPase and bromodomain factor ATAD2/ANCCA is overexpressed in many types of cancer, but how it contributes to tumorigenesis is not understood. Here, we report that the homolog Yta7 is a deposition factor for the centromeric histone H3 variant Cse4 at the centromere in yeast. Yta7 regulates the levels of centromeric Cse4 in that causes reduced Cse4 deposition, whereas overexpression causes increased Cse4 deposition. Yta7 coimmunoprecipitates with Cse4 and is associated with the centromere, arguing for a direct role of Yta7 in Cse4 deposition. Furthermore, increasing centromeric Cse4 levels by overexpression requires the activity of Scm3, the centromeric nucleosome assembly factor. Importantly, Yta7 interacts in vivo with Scm3, indicating that Yta7 is a cochaperone for Scm3 The absence of Yta7 causes defects in growth and chromosome segregation with mutations in components of the inner kinetochore (CTF19/CCAN, Mif2, Cbf1). Since Yta7 is an AAA ATPase and potential hexameric unfoldase, our results suggest that it may unfold the Cse4 histone and hand it over to Scm3 for subsequent deposition in the centromeric nucleosome. Furthermore, our findings suggest that ATAD2 overexpression may enhance malignant transformation in humans by misregulating centromeric CENP-A levels, thus leading to defects in kinetochore assembly and chromosome segregation.