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 Saccharomyces cerevisiae homolog Yta7^ATAD2 is a deposition factor for the centromeric histone H3 variant Cse4^CENP-A at the centromere in yeast. Yta7^ATAD2 regulates the levels of centromeric Cse4^CENP-A in that yta7∆ causes reduced Cse4^CENP-A deposition, whereas YTA7 overexpression causes increased Cse4^CENP-A deposition. Yta7^ATAD2 coimmunoprecipitates with Cse4^CENP-A and is associated with the centromere, arguing for a direct role of Yta7^ATAD2 in Cse4^CENP-A deposition. Furthermore, increasing centromeric Cse4^CENP-A levels by YTA7 overexpression requires the activity of Scm3^HJURP, the centromeric nucleosome assembly factor. Importantly, Yta7^ATAD2 interacts in vivo with Scm3^HJURP, indicating that Yta7^ATAD2 is a cochaperone for Scm3^HJURP The absence of Yta7 causes defects in growth and chromosome segregation with mutations in components of the inner kinetochore (CTF19/CCAN, Mif2^CENP-C, Cbf1). Since Yta7^ATAD2 is an AAA⁺ ATPase and potential hexameric unfoldase, our results suggest that it may unfold the Cse4^CENP-A histone and hand it over to Scm3^HJURP 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.

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Journal Article | Research Support, Non-U.S. Gov't

Authors

Shahnejat-Bushehri S, Ehrenhofer-Murray AE

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